1-aryl-5-alkyl pyrazole derivative compounds, processes of making and methods of using thereof

ABSTRACT

Provided are 1-aryl-5-alkyl pyrazole compounds, of formula (I): 
                         
wherein: R 1  is hydrogen, cyano, halogen, R 8 , formyl, —C(O)R 8 , —C(O)OR 8 , —C(O)NR 9 R 10 , or —C(S)NH 2 ; R 2  is R 8  or —S(O) m R 11 ; R 3  is methyl, ethyl or C 1 -C 4  haloalkyl; R 4 , R 5  and R 7  are independently hydrogen, halogen, alkyl, haloalkyl, cyano or nitro; R 6  is halogen, alkyl, haloalkyl, alkoxy, haloalkyloxy, cyano, nitro, —C(O)R 12 , —S(O) n R 12  or SF 5 ; Z is a nitrogen atom or C—R 13 ; R 8  is alkyl, haloalkyl, cycloalkyl or halocycloalkyl; R 9  is hydrogen, alkyl, haloalkyl or alkoxy; R 10  is hydrogen, alkyl, haloalkyl or alkoxy; R 11  is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl or cycloalkyl; R 12  is alkyl or haloalkyl; R 13  is hydrogen, halogen, cyano, nitro, alkyl, haloalkyl, alkoxy or haloalkoxy; m is 0, 1 or 2; and n is 0, 1 or 2; or a salt thereof, the method of making compounds of formula (I) and the use of these compounds against ectoparasites, endoparasites and pests.

INCORPORATION BY REFERENCE

This application claims priority to U.S. Provisional Application Ser.No. 60/818,585, filed Jul. 5, 2006 and Ser. No. 60/925,913 filed Apr.24, 2007.

Any foregoing applications, and all documents cited therein or duringtheir prosecution (“application cited documents”) and all documentscited or referenced in the application cited documents, and alldocuments cited or referenced herein (“herein cited documents”), and alldocuments cited or referenced in herein cited documents, together withany manufacturer's instructions, descriptions, product specifications,and product sheets for any products mentioned herein or in any documentincorporated by reference herein, are hereby incorporated herein byreference, and may be employed in the practice of the invention.

FIELD OF THE INVENTION

The present invention relates to 1-aryl-5-alkyl pyrazole compounds, ofgeneral formula (I):

wherein:

-   R₁, R₂, R₃, R₄, R₅, R₆, R₇ and p are as defined below; or a salt    thereof and the use of these compounds against ectoparasites such as    insects, arthropods and acarina.

BACKGROUND OF THE INVENTION

Animals such as mammals and birds are often susceptible to parasiteinfestations. These parasites may be ectoparasites, such as insects, andendoparasites such as filariae and worms.

Domesticated animals, such as cats and dogs, are often infested with oneor more of the following ectoparasites:

-   -   fleas (Ctenocephalides felis, Ctenocephalides sp. and the like),    -   ticks (Rhipicephalus sp., Ixodes sp., Dermacentor sp., Amblyomma        sp. and the like),    -   mites (Demodex sp., Sarcoptes sp., Otodectes sp. and the like),    -   lice (Trichodectes sp., Cheyletiella sp., Linognathus sp., and        the like), and    -   flies (Hematobia sp., Musca sp., Stomoxys sp., Dermatobia sp.,        Cochliomyia sp., mosquitoes (family Culicidae) and the like).

Fleas are a particular problem because not only do they adversely affectthe health of the animal or human, but they also cause a great deal ofpsychological stress. Moreover, fleas are also vectors of pathogenicagents in animals, such as dog tapeworm (Dipylidium caninum), and mayalso transmit pathogens to humans.

Similarly, ticks are also harmful to the physical and psychologicalhealth of the animal or human. However, the most serious problemassociated with ticks is that they are the vector of pathogenic agents,which cause diseases in both humans and animals Major diseases which arecaused by ticks include borreliosis (Lyme disease caused by Borreliaburgdorferi), babesiosis (or piroplasmosis caused by Babesia sp.) andrickettsiosis (also known as Rocky Mountain spotted fever). Ticks alsorelease toxins which cause inflammation or paralysis in the host.Occasionally, these toxins are fatal to the host, such as in the case ofthe Australian paralysis tick, Ixodes holocyclus.

Moreover, mites and lice are particularly difficult to combat sincethere are very few active substances which act on these parasites andthey require frequent treatment.

Likewise, farm animals are also susceptible to parasite infestations.For example, cattle are affected by a large number of parasites.Likewise, arthropod pests, such as fleas, lice and ticks, and mitesinfest poultry. A parasite that is very prevalent among farm animals isthe tick genus Boophilus, especially those of the species microplus(cattle tick), decoloratus and anulatus. Ticks, such as Boophilusmicroplus, are particularly difficult to control because they live inthe pasture where the farm animals graze. Other important parasites ofcattle and sheep are listed as follows in order of decreasingimportance:

-   (a) myiases such as Dermatobia hominis (known as Berne in Brazil),    Hypoderma, and Cochlyomia hominivorax (green bottle); sheep myiases    such as Lucilia sericata, Lucilia cuprina (known as blowfly strike    in Australia, New Zealand and South Africa). These are flies whose    larva constitutes the animal parasite;-   (b) flies proper, namely those whose adult constitutes the parasite,    such as Haematobia irritans (horn fly);-   (c) lice such as Linognathus vituli etc.; and-   (d) mites such as Sarcoptes scabiei and Psoroptes ovis.

The compounds of the invention may also be useful against householdpests including, but not limited to, cockroach, Blatella sp., clothesmoth, Tineola sp., carpet beetle, Attagenus sp. and the housefly Muscadomestica and against Solenopsis invicta (imported fire ants), termites,and the like.

These compounds may further be useful against agricultural pests such asaphids (Acyrthiosiphon sp.), locusts, and boll weevils as well asagainst insect pests that attack stored grains, such as Tribolium sp.,and against immature stages of insects living on plant tissue.

The above list is not exhaustive and other ectoparasites are well knownin the art to be harmful to animals, humans and crops.

Compounds that exhibit a degree of activity against a wide range ofectoparasites including arthopods and insects are known in the art. Onesuch class of compounds is the arylpyrazoles which are referred to, forexample, in U.S. Pat. Nos. 5,122,530; 5,246,255; 5,576,429; 5,885,607;6,010,710; 6,083,519; 6,096,329; 6,685,954; EP 0 234 119 and EP 0 295117 (U.S. Pat. Nos. 5,232,940; 5,547,974; 5,608,077; 5,714,191;5,916,618 and 6,372,774); EP 0 352 944 (U.S. Pat. No. 4,963,575); EP 0780 378 (U.S. Pat. Nos. 5,817,688; 5,922,885; 5,994,386; 6,124,339;6,180,798 and 6,395,906); EP 0 846 686 (U.S. Pat. No. 6,069,157); and WO98/28278.

The arylpyrazoles are known to possess excellent activity againstinsects, such as fleas and ticks. Fipronil is a specific type of1-N-aryl pyrazole that is particularly effective against fleas and ticksand is the active ingredient in Frontline® and Frontline Plus®. Fipronilhas the following chemical structure:

However, ectoparasiticidal agents can vary in their effectiveness to aparticular parasite as well as vary in their cost of production.Moreover, the results of ectoparasiticidal agents may not always besatisfactory because of, for example, the development of resistance bythe parasite to the therapeutic agent, as is the case, for example, withcarbamates, organophosphorus compounds and pyrethroids.

It is known from the literature that hydrazines may react with1,3-dicarbonyl compounds to form pyrazoles. For example, U.S. Pat. No.6,750,230 refers to the synthesis of pyrazoles unsubstituted at the oneposition or substituted by an alkylene group from 1,3-diketones. WO01/32663 refers to the synthesis of pyrazolecarboxylic acid tricycliccompounds. WO 03/057674 refers to the synthesis of4-sulfide/sulfoxidepyrazoles bearing a substituted alkyl group at the1-position, which may be prepared from the reaction of a2-thio-1,3-diketone with a hydrazine (see page 24, Reaction Scheme 1).However, there appeared to be no examples where this 2-thio-1,3-diketonederivative was made directly by reacting a sulfenyl halide reagent with1,3-diketone compounds.

WO 02/058690 and US 2004/0876627 refer to the synthesis of pyrazolesbearing a (2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethylsubstituent by reaction between a 1,3-diketone and phenylhydrazinebearing the 1-hydroxy-1-(trifluoromethyl)ethyl substituent (Scheme 4,page 11, US 2004/0876627). The synthesis of a specific compound by thismethod,5-methyl-1-[(1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1H-pyrazole-3-carboxylicacid ethyl ester is mentioned (US 2004/0876627, pages 23-24, Example 8).However, there appeared to be no examples where a 3,4,5-disubstitutedpyrazole is prepared except in the presence of a 5-amino group or whenall three substitutions are the same (methyl).

Synthesis of 3-ester-4-unsubstituted pyrazoles is also referred to in US2005/00020564 (page 10, Scheme 3).

However, a general problem with obtaining pyrazoles by reactinghydrazines with 1,3-dicarbonyl compounds is the difficulty in preparingcompounds with regioselectivity, as there is competition in the reactionat the different carbonyl groups of the 1,3-dicarbonyl compound

Thus, there is still a need in the art for more effective and rapidlyacting antiparasitic composition for the treatment and protection ofanimals, e.g. mammals, fish and birds, from a wide range of parasites.There is a need in the art for an antiparasitic formulation which iseasy to use on any type of domestic animal, irrespective of its size andthe nature of its coat and which do not need to be sprinkled over theentire body of the mammal, fish or bird. Further, the formulation shouldbe effective for a long period of time thereby reducing the number oftimes it has to be applied.

Citation or identification of any document in this application is not anadmission that such document is available as prior art to the presentinvention.

OBJECTS AND SUMMARY OF THE INVENTION

The invention provides, and it is an object of the invention to provide,novel compounds, compositions and uses thereof for the treatment orprophylaxis of parasites of animals (either wild or domesticated), e.g.,livestock and companion animals such as cats, dogs, horses, chickens,sheep, goats, pigs, turkeys and cattle, with the aim of ridding thesehosts of parasites commonly encountered by such animals.

Accordingly, it is an object of the invention to not encompass withinthe invention any previously known compounds, compositions, and usessuch that applicant(s) reserve the right and hereby disclose adisclaimer of any previously known compounds, compositions and uses.

The invention also provides for effective and long lasting destructionof ectoparasites, such as fleas, ticks, mites, mosquitoes, flies andlice. The invention may also be effective against endoparasites,cestodes, nematodes, such as filariae, and roundworms of the digestivetract of animals and humans.

The 1-aryl-5-alkyl pyrazole compounds of the invention, alone or incombination, are able to provide superior protection againstectoparasites which may include speed of efficacy, long lasting efficacy(e.g. for a period of at least one month) and enhanced selectivity.

One aspect of the invention is to provide a 1-aryl-5-alkyl pyrazolecompound of the formula (I):

wherein:

-   -   R₁ is hydrogen, cyano, halogen, R₈, formyl, —C(O)R₈, —C(O)OR₈,        —C(O)NR₉R₁₀, or —C(S)NH₂;    -   R₂ is R₈ or —S(O)_(m)R₁₁;    -   R₃ is methyl, ethyl or C₁-C₄ haloalkyl;    -   R₄, R₅ and R₇ are independently hydrogen, halogen, alkyl,        haloalkyl, cyano or nitro;    -   R₆ is halogen, alkyl, haloalkyl, alkoxy, haloalkyloxy, cyano,        nitro, —C(O)R₁₂, —S(O)_(n)R₁₂ or SF₅;    -   Z is a nitrogen atom or C—R₁₃;    -   R₈ is alkyl, haloalkyl, cycloalkyl or halocycloalkyl;    -   R₉ is hydrogen, alkyl, haloalkyl or alkoxy;    -   R₁₀ is hydrogen, alkyl, haloalkyl or alkoxy;    -   R₁₁ is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl or cycloalkyl;    -   R₁₂ is alkyl or haloalkyl;    -   R₁₃ is hydrogen, halogen, cyano, nitro, alkyl, haloalkyl, alkoxy        or haloalkoxy;    -   m is 0, 1 or 2; and    -   n is 0, 1 or 2; or    -   a salt thereof.

A second aspect of the invention, provides for a process for thepreparation of a compound of formula (I), or a pharmaceutically,veterinarily or agriculturally acceptable salt thereof, or apharmaceutically, veterinarily or agriculturally acceptable solvate(including hydrate) of either entity.

A third aspect of the present invention is to provide compositions fortreatment of animals against ectoparasites, wherein the compositionscomprise the compounds of the invention and an acceptable carrier.

A fourth aspect of the invention is to provide pesticidal methods of useof the 1-aryl-5-alkyl pyrazole compounds/compositions of the inventionagainst ectoparasites (e.g. arthropods, acarina and insects), inveterinary medicine or livestock husbandry, in public health, or inagricultural or horticultural crops.

A fifth aspect of the present invention is to provide compounds withhigh activity and improved safety to the user and the environment, whichare obtained by optimization of chemical, physical and biologicalproperties such as solubility, melting point, stability, electronic andsteric parameters, and the like.

A sixth aspect of the present invention is to provide a method forpreventing or interrupting the transmission of parasite-borne diseasesfrom an actual or putative amplifying or incipient host, such as ananimal or bird (wild or domesticated) or human, to a second actual orputative amplifying or incipient host, such as an animal, bird or human,using a composition comprising the 1-aryl-5-alkyl pyrazole compounds ofthe invention.

A seventh aspect of the present invention is to provide novelintermediate compounds for the production of the compounds of formula(I).

Finally, it has been found that the novel compounds of the formula (I)have strongly pronounced biological properties and are suitableespecially for controlling animal pests, in particular insects,arachnids and nematodes encountered in agriculture, in forests, in theprotection of stored products and in the protection of materials, andalso in the hygiene sector.

For the purposes of this application, unless otherwise stated in thespecification, the following terms have the definitions cited below:

-   (1) Alkyl refers to both straight and branched carbon chains;    references to individual alkyl groups are specific for the straight    chain (e.g. butyl=n-butyl). In one embodiment of alkyl, the number    of carbons atoms is 1-20, in another embodiment of alkyl, the number    of carbon atoms is 1-8 carbon atoms and in yet another embodiment of    alkyl, the number of carbon atoms is 1-4 carbon atoms. Other ranges    of carbon numbers are also contemplated depending on the location of    the alkyl moiety on the molecule;-   (2) Alkenyl refers to both straight and branched carbon chains which    have at least one carbon-carbon double bond. In one embodiment of    alkenyl, the number of double bonds is 1-3, in another embodiment of    alkenyl, the number of double bonds is one. In one embodiment of    alkenyl, the number of carbons atoms is 2-20, in another embodiment    of alkenyl, the number of carbon atoms is 2-8 and in yet another    embodiment of alkenyl, the number of carbon atoms is 2-4. Other    ranges of carbon-carbon double bonds and carbon numbers are also    contemplated depending on the location of the alkenyl moiety on the    molecule;-   (3) Alkynyl refers to both straight and branched carbon chains which    have at least one carbon-carbon triple bond. In one embodiment of    alkynyl, the number of triple bonds is 1-3; in another embodiment of    alkynyl, the number of triple bonds is one. In one embodiment of    alkynyl, the number of carbons atoms is 2-20, in another embodiment    of alkynyl, the number of carbon atoms is 2-8 and in yet another    embodiment of alkynyl, the number of carbon atoms is 2-4. Other    ranges of carbon-carbon double bonds and carbon numbers are also    contemplated depending on the location of the alkenyl moiety on the    molecule;-   (4) Aryl refers to a C₆-C₁₀ aromatic ring structure. In one    embodiment of aryl, the moiety is phenyl, naphthyl,    tetrahydronapthyl, phenylcyclopropyl and indanyl; in another    embodiment of aryl, the moiety is phenyl.-   (5) Alkoxy refers to —O-alkyl, wherein alkyl is as defined in (1);-   (6) Alkanoyl refers to formyl (—C(═O)H) and —C(═O)-alkyl, wherein    alkyl is as defined in (1);-   (7) Alkanoyloxy refers to —O—C(═O)-alkyl, wherein alkanoyl is as    defined in (6);-   (8) Alkanoylamino refers to —NH₂—C(═O)-alkyl, wherein alkanoyl is as    defined in (6) and the amino (NH₂) moiety can be substituted by    alkyl as defined in (1);-   (9) Aminocarbonyl refers to —NH₂—C(═O), wherein the amino (NH₂)    moiety can be substituted by alkyl as defined in (1);-   (10) Alkoxycarbonyl refers to —C(═O)—O-alkyl, wherein alkoxy is as    defined in (5);-   (11) Alkenoyl refers to —C(═O)-alkenyl, wherein alkenyl is as    defined in (2);-   (12) Alkynoyl refers to —C(═O)-alkynyl, wherein alkynyl is as    defined in (3);-   (13) Aroyl refers to —C(═O)-aryl, wherein aryl is as defined above;-   (14) Cyclo as a prefix (e.g. cycloalkyl, cycloalkenyl, cycloalkynyl)    refers to a saturated or unsaturated cyclic ring structure having    from three to eight carbon atoms in the ring the scope of which is    intended to be separate and distinct from the definition of aryl    above. In one embodiment of cyclo, the range of ring sizes is 4-7    carbon atoms; in another embodiment of cyclo the range of ring sizes    is 3-4. Other ranges of carbon numbers are also contemplated    depending on the location of the cyclo-moiety on the molecule;-   (15) Halogen means the atoms fluorine, chlorine, bromine and iodine.    The designation of “halo” (e.g. as illustrated in the term    haloalkyl) refers to all degrees of substitutions from a single    substitution to a perhalo substitution (e.g. as illustrated with    methyl as chloromethyl (—CH₂Cl), dichloromethyl (—CHCl₂),    trichloromethyl (—CCl₃));-   (16) Heterocycle, heterocyclic or heterocyclo refer to fully    saturated or unsaturated, including aromatic (i.e. “heteroaryl”)    cyclic groups, for example, 4 to 7 membered monocyclic, 7 to 11    membered bicyclic, or 10 to 15 membered tricyclic ring systems,    which have at least one heteroatom in at least one carbon    atom-containing ring. Each ring of the heterocyclic group containing    a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from    nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen    and sulfur heteroatoms may optionally be oxidized and the nitrogen    heteroatoms may optionally be quaternized. The heterocyclic group    may be attached at any heteroatom or carbon atom of the ring or ring    system.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl,pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl,imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl,thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl,furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl,azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl,tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane andtetrahydro-1,1-dioxothienyl, triazolyl, triazinyl, and the like.

Exemplary bicyclic heterocyclic groups include indolyl, benzothiazolyl,benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl,tetra-hydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl,cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (suchas furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl),dihydroisoindolyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl and the like.

Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl,phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

Unless otherwise specifically noted or apparent by context, “activeagent” or “active ingredient” or “therapeutic agent” as used in thisspecification, means a 1-aryl-5-alkyl pyrazole compound of the invention

It is also noted that this disclosure and in the claims and/orparagraphs, the term “1-aryl-5-alkyl pyrazole compound” as used todescribe the invention is intended to include all stereoisomers andcrystalline forms (which includes hydrated forms, polymorphic forms andamorphous forms with up to 15% by weight crystalline structure) thereof.

It is noted that in this disclosure and in the claims, terms such as“comprises”, “comprised”, “comprising” and the like can have the meaningattributed to it in U.S. Patent law; e.g., they can mean “includes”,“included”, “including”, and the like; and that terms such as“consisting essentially of” and “consists essentially of” have themeaning ascribed to them in U.S. Patent law, e.g., they allow forelements not explicitly recited, but exclude elements that are found inthe prior art or that affect a basic or novel characteristic of theinvention.

It is further noted that the invention does not intend to encompasswithin the scope of the invention any previously disclosed compound,product, process of making the product or method of using the product,which meets the written description and enablement requirements of theUSPTO (35 U.S.C. 112, first paragraph) or the EPO (Article 83 of theEPC), such that applicant(s) reserve the right and hereby disclose adisclaimer of any previously described product, method of making theproduct or process of using the product. It is therefore an intention ofthe invention to not explicitly cover compounds, products, processes ofmaking products or compounds, or methods of using products or compoundsthat are explicitly disclosed in the prior art or whose novelty isdestroyed by prior art, including without limitation any prior artherein mentioned, including without limitation U.S. Pat. Nos. 5,122,530;5,246,255; 5,576,429; 5,885,607; 6,010,710; 6,083,519; 6,096,329;6,685,954; EP 0 234 119 and EP 0 295 117 (eq. to U.S. Pat. Nos.5,232,940; 5,547,974; 5,608,077; 5,714,191; 5,916,618 and 6,372,774); EP0 352 944 (eq. to U.S. Pat. No. 4,963,575); EP 0 780 378 (eq. to U.S.Pat. Nos. 5,817,688; 5,922,885; 5,994,386; 6,124,339; 6,180,798 and6,395,906); EP 0 846 686 (eq. to U.S. Pat. No. 6,069,157); and WO98/28278; and, applicant(s) explicitly reserve the right to introduceinto any claim a disclaimer as to any previously disclosed compound,product, process of making the product or method of using the product.Specifically, the compounds of formula (I) and (Ia) are not intended toencompass fipronil or previously disclosed derivatives of fipronil.

These and other embodiments are disclosed or are apparent from andencompassed by, the following Detailed Description.

DETAILED DESCRIPTION

A first aspect of the invention provides a 1-aryl-5-alkyl pyrazolecompound of formula (I):

wherein:

-   -   R₁ is hydrogen, cyano, halogen, R₈, formyl, —C(O)R₈, —C(O)OR₈,        —C(O)NR₉R₁₀, or —C(S)NH₂;    -   R₂ is R₈ or —S(O)_(m)R₁₁;    -   R₃ is methyl, ethyl or C₁-C₄ haloalkyl;    -   R₄, R₅ and R₇ are independently hydrogen, halogen, alkyl,        haloalkyl, cyano or nitro;    -   R₆ is halogen, alkyl, haloalkyl, alkoxy, haloalkyloxy, cyano,        nitro, —C(O)R₁₂, —S(O)_(n)R₁₂ or SF₅;    -   Z is a nitrogen atom or C—R₁₃;    -   R₈ is alkyl, haloalkyl, cycloalkyl or halocycloalkyl;    -   R₉ is hydrogen, alkyl, haloalkyl or alkoxy;    -   R₁₀ is hydrogen, alkyl, haloalkyl or alkoxy;    -   R₁₁ is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl or cycloalkyl;    -   R₁₂ is alkyl or haloalkyl;    -   R₁₃ is hydrogen, halogen, cyano, nitro, alkyl, haloalkyl, alkoxy        or haloalkoxy;    -   m is 0, 1 or 2; and    -   n is 0, 1 or 2; or    -   a salt thereof.

A second aspect of the invention provides a 1-aryl-5-alkyl pyrazolecompound of formula (I) wherein:

-   -   R₃ is methyl or ethyl; and    -   R₁, R₂, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, m and n are        as defined above; or    -   a salt thereof.

A third aspect of the invention provides a 1-aryl-5-alkyl pyrazolecompound of formula (I) wherein:

-   -   R₃ is C₁-C₄ haloalkyl; and    -   R₁, R₂, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, m and n are        as defined above; or    -   a salt thereof.

Another embodiment of the first aspect of the invention provides a1-aryl-5-alkyl pyrazole compound of formula (I):

wherein:

-   -   R₁ is hydrogen, cyano, halogen, R₈, formyl, —C(O)R₈, —C(O)OR₈,        —C(O)NR₉R₁₀, or —C(S)NH₂;    -   R₂ is R₈ or —S(O)_(m)R₁₁,    -   R₃ is a methyl, ethyl or C₁-C₄ haloalkyl,    -   R₄, R₅ and R₇ are independently hydrogen, halogen, alkyl,        haloalkyl, cyano or nitro;    -   R₆ is halogen, alkyl, haloalkyl, alkoxy, haloalkyloxy, cyano,        nitro, —C(O)R₁₂, —S(O)_(n)R₁₂ or SF₅;    -   Z is a nitrogen atom or C—R₁₃;    -   R₈ is alkyl, haloalkyl, cycloalkyl or halocycloalkyl;    -   R₉ is hydrogen, alkyl, haloalkyl or alkoxy;    -   R₁₀ is hydrogen, alkyl, haloalkyl or alkoxy;    -   R₁₁ is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl or cycloalkyl;    -   R₁₂ is alkyl or haloalkyl;    -   R₁₃ is hydrogen, halogen, cyano, nitro, alkyl, haloalkyl, alkoxy        or haloalkoxy;    -   m is 0, 1 or 2; and    -   n is 0, 1 or 2; or    -   a salt thereof.

Another embodiment of the first aspect of the invention provides a1-aryl-5-alkyl pyrazole compound of formula (I) is:

-   -   R₁ is hydrogen, cyano, halogen, R₈, formyl, —C(O)R₈, —C(O)OR₈,        —C(O)NR₉R₁₀, or —C(S)NH₂;    -   R₂ is alkyl, haloalkyl or —S(O)_(m)R₁₁;    -   R₃ is a methyl, ethyl or C₁-C₄ haloalkyl,    -   R₄, R₅ and R₇ are independently hydrogen, halogen, alkyl,        haloalkyl, cyano or nitro;    -   R₆ is halogen, alkyl, haloalkyl, alkoxy, haloalkyloxy, cyano,        nitro, —C(O)R₁₂, —S(O)_(n)R₁₂ or —SF₅;    -   Z is a nitrogen atom or C—R₁₃;    -   R₈ is alkyl, haloalkyl, cycloalkyl or halocycloalkyl;    -   R₉ is hydrogen, alkyl, haloalkyl or alkoxy;    -   R₁₀ is hydrogen, alkyl, haloalkyl or alkoxy;    -   R₁₁ is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl or cycloalkyl;    -   R₁₂ is alkyl or haloalkyl;    -   R₁₃ is hydrogen, halogen, cyano, nitro, alkyl, haloalkyl, alkoxy        or haloalkoxy;    -   m is 0, 1 or 2; and    -   n is 0, 1 or 2; or    -   a salt thereof.

Another embodiment of the first aspect of the invention provides a1-aryl-5-alkyl pyrazoles of formula (I) wherein:

-   -   R₁ is hydrogen, cyano, halogen, R₈, formyl, —C(O)R₈, —C(O)OR₈,        —C(O)NR₉R₁₀, or —C(S)NH₂;    -   R₂ is C₁-C₄ alkyl, C₁-C₄ haloalkyl, or —S(O)_(m)R₁₁,    -   R₃ is a methyl, ethyl or C₁-C₄ haloalkyl,    -   R₄, R₅ and R₇ are independently hydrogen, halogen, C₁-C₄ alkyl,        C₁-C₄ haloalkyl, cyano or nitro;    -   R₆ is halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄        haloalkyloxy, cyano, nitro, —C(O)R₁₂, —S(O)_(n)R₁₂ or SF₅;    -   Z is a nitrogen atom or C—R₁₃;    -   R₈ is C₁-C₄ alkyl, C₁-C₄ haloalkyl or cycloalkyl optionally        substituted with one or more halogens;    -   R₉ is hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl or C₁-C₄ alkoxy;    -   R₁₀ is hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl or C₁-C₄ alkoxy;    -   R₁₁ is C₁-C₄alkyl, C₁-C₄ haloalkyl, C₂-C₄alkenyl, C₂-C₄        haloalkenyl, C₂-C₄ alkynyl, C₂-C₄ haloalkynyl or cycloalkyl;    -   R₁₂ is C₁-C₄ alkyl or C₁-C₄ haloalkyl;    -   R₁₃ is hydrogen, halogen, cyano, nitro, C₁-C₄ alkyl, C₁-C₄        haloalkyl, C₁-C₄ alkoxy or C₁-C₄ haloalkoxy;    -   m is 0, 1 or 2; and    -   n is 0, 1 or 2; or    -   a salt thereof.

Another embodiment of the first aspect of the invention provides a1-aryl-5-alkyl pyrazoles of formula (I) wherein:

-   -   R₁ is hydrogen, cyano, fluoro, chloro, R₈, formyl, —C(O)R₈,        —C(O)OR₈, —C(O)NR₉R₁₀, or —C(S)NH₂;    -   R₂ is C₁-C₂ alkyl, C₁-C₂ fluoroalkyl, C₁-C₂ chloroalkyl or        —S(O)_(m)R₁₁;    -   R₃ is a methyl, ethyl optionally substituted with one to three        halogens;    -   R₄, R₅ and R₇ are independently selected from the group        consisting of hydrogen, fluoro, chloro, C₁-C₂ alkyl,        C₁-C₂-fluoroalkyl, C₁-C₂ chloroalkyl, cyano and nitro;    -   R₆ is fluoro, chloro, C₁-C₂alkyl, C₁-C₂-fluoroalkyl,        C₁-C₂-chloroalkyl, C₁-C₂alkoxy, C₁-C₂ fluoroalkyloxy, C₁-C₂        chloroalkyloxy, cyano, nitro, —C(O)R₁₂, —S(O)_(n)R₁₂ or SF₅;    -   Z is a nitrogen atom or C—R₁₃;    -   R₈ is C₁-C₂alkyl, C₁-C₂-fluoroalkyl or C₁-C₂-chloroalkyl;    -   R₉ is hydrogen, C₁-C₂alkyl, C₁-C₂-fluoroalkyl, C₁-C₂-chloroalkyl        or C₁-C₂alkoxy;    -   R₁₀ is hydrogen, C₁-C₂ alkyl, C₁-C₂ fluoroalkyl, C₁-C₂        chloroalkyl or C₁-C₂ alkoxy;    -   R₁₁ is C₁-C₂alkyl, C₁-C₂-fluoroalkyl, C₁-C₂-chloroalkyl,        C₂-C₄alkenyl, C₂-C₄ fluoroalkenyl, C₂-C₄ chloroalkenyl, C₂-C₄        alkynyl, C₂-C₄ fluoroalkynyl or C₂-C₄ chloroalkynyl;    -   R₁₂ is C₁-C₂alkyl, C₁-C₂-fluoroalkyl or C₁-C₂-chloroalkyl;    -   R₁₃ is hydrogen, fluoro, chloro, cyano, nitro, C₁-C₂alkyl,        C₁-C₂-fluoroalkyl, C₁-C₂ chloroalkyl, C₁-C₂ alkoxy, C₁-C₂        fluoroalkoxy or C₁-C₂ chloroalkoxy;    -   m is 0, 1 or 2; and    -   n is 0, 1 or 2; or    -   a salt thereof.

Another embodiment of the first aspect of the invention, wherein Z isC—R₁₃, provides a 1-aryl-5-alkyl pyrazoles of formula (I) wherein:

-   -   R₁ is cyano;    -   R₂ is —S(O)_(m)R₁₁;    -   R₃ is a methyl, ethyl optionally substituted with one to three        halogens;    -   R₄, R₅, R₇ are independently hydrogen or halogen;    -   R₆ is C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy or SF₅;    -   R₁₁ is C₁-C₄ haloalkyl;    -   R₁₃ is C₁-C₄ alkyl optionally substituted with one or more        fluoro or chloro or halogen; and    -   m is 0, 1 or 2; or    -   a salt thereof.

Another embodiment of the first aspect of the invention, wherein Z isC—R₁₃, provides a 1-aryl-5-alkyl pyrazoles of formula (I) wherein:

-   -   R₁ is cyano;    -   R₂ is —S(O)_(m)R₁₁;    -   R₃ is a methyl, ethyl, —CH₂F or —CHF₂;    -   R₄, R₅, and R₇ are independently hydrogen or halogen;    -   R₆ is —CF₃, —OCF₃ or —SF₅;    -   R₁₁ is —CF₃, —CClF₂ or —CCl₂F;    -   R₁₃ is methyl, chloro or fluoro; and    -   m is 0, 1 or 2; or    -   a salt thereof.

Another embodiment of the first aspect of the invention wherein Z isC—R₁₃, provides a 1-aryl-5-alkyl pyrazoles of formula (I) wherein:

-   -   R₁ is cyano;    -   R₂ is —S(O)_(m)R₁₁;    -   R₃ is a methyl, ethyl, —CH₂F or —CHF₂;    -   R₄ is hydrogen, Cl or F;    -   R₅ and R₇ are both hydrogen;    -   R₆ is —CF₃, —OCF₃ or —SF₅;    -   R₁₁ is —CF₃, —CClF₂ or —CCl₂F;    -   R₁₃ is methyl, chloro or fluoro; and    -   m is 0, 1 or 2; or    -   a salt thereof.

Another embodiment of the second aspect of the invention provides a1-aryl-5-alkyl pyrazole compound of formula (I):

wherein:

-   -   R₁ is hydrogen, cyano, halogen, R₈, formyl, —C(O)R₈, —C(O)OR₈,        —C(O)NR₉R₁₀, or —C(S)NH₂;    -   R₂ is R₈ or —S(O)_(m)R₁₁,    -   R₃ is a methyl or ethyl,    -   R₄, R₅ and R₇ are independently hydrogen, halogen, alkyl,        haloalkyl, cyano or nitro;    -   R₆ is halogen, alkyl, haloalkyl, alkoxy, haloalkyloxy, cyano,        nitro, —C(O)R₁₂, —S(O)_(n)R₁₂ or SF₅;    -   Z is a nitrogen atom or C—R₁₃;    -   R₈ is alkyl, haloalkyl, cycloalkyl or halocycloalkyl;    -   R₉ is hydrogen, alkyl, haloalkyl or alkoxy;    -   R₁₀ is hydrogen, alkyl, haloalkyl or alkoxy;    -   R₁₁ is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl or cycloalkyl;    -   R₁₂ is alkyl or haloalkyl;    -   R₁₃ is hydrogen, halogen, cyano, nitro, alkyl, haloalkyl, alkoxy        or haloalkoxy;    -   m is 0, 1 or 2; and    -   n is 0, 1 or 2; or    -   a salt thereof.

Another embodiment of the second aspect of the invention provides a1-aryl-5-alkyl pyrazole compound of formula (I) is:

-   -   R₁ is hydrogen, cyano, halogen, R₈, formyl, —C(O)R₈, —C(O)OR₈,        —C(O)NR₉R₁₀, or —C(S)NH₂;    -   R₂ is alkyl, haloalkyl or —S(O)_(m)R₁₁,    -   R₃ is a methyl or ethyl,    -   R₄, R₅ and R₇ are independently hydrogen, halogen, alkyl,        haloalkyl, cyano or nitro;    -   R₆ is halogen, alkyl, haloalkyl, alkoxy, haloalkyloxy, cyano,        nitro, —C(O)R₁₂, —S(O)_(n)R₁₂ or —SF₅;    -   Z is a nitrogen atom or C—R₁₃;    -   R₈ is alkyl, haloalkyl, cycloalkyl or halocycloalkyl;    -   R₉ is hydrogen, alkyl, haloalkyl or alkoxy;    -   R₁₀ is hydrogen, alkyl, haloalkyl or alkoxy;    -   R₁₁ is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl or cycloalkyl;    -   R₁₂ is alkyl or haloalkyl;    -   R₁₃ is hydrogen, halogen, cyano, nitro, alkyl, haloalkyl, alkoxy        or haloalkoxy;    -   m is 0, 1 or 2; and    -   n is 0, 1 or 2; or    -   a salt thereof.

Another embodiment of the second aspect of the invention provides a1-aryl-5-alkyl pyrazoles of formula (I) wherein:

-   -   R₁ is hydrogen, cyano, halogen, R₈, formyl, —C(O)R₈, —C(O)OR₈,        —C(O)NR₉R₁₀, or —C(S)NH₂;    -   R₂ is C₁-C₄ alkyl, C₁-C₄ haloalkyl or —S(O)_(m)R₁₁,    -   R₃ is methyl or ethyl,    -   R₄, R₅ and R₇ are independently hydrogen, halogen, C₁-C₄ alkyl,        C₁-C₄ haloalkyl, cyano or nitro;    -   R₆ is halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄        haloalkyloxy, cyano, nitro, —C(O)R₁₂, —S(O)_(n)R₁₂ or SF₅;    -   Z is a nitrogen atom or C—R₁₃;    -   R₈ is C₁-C₄ alkyl, C₁-C₄ haloalkyl or cycloalkyl optionally        substituted with one or more halogens;    -   R₉ is hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl or C₁-C₄ alkoxy;    -   R₁₀ is hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl or C₁-C₄ alkoxy;    -   R₁₁ is C₁-C₄alkyl, C₁-C₄ haloalkyl, C₂-C₄alkenyl, C₂-C₄        haloalkenyl, C₂-C₄ alkynyl, C₂-C₄ haloalkynyl or cycloalkyl;    -   R₁₂ is C₁-C₄ alkyl or C₁-C₄ haloalkyl;    -   R₁₃ is hydrogen, halogen, cyano, nitro, C₁-C₄ alkyl, C₁-C₄        haloalkyl, C₁-C₄ alkoxy or C₁-C₄ haloalkoxy;    -   m is 0, 1 or 2; and    -   n is 0, 1 or 2; or    -   a salt thereof.

Another embodiment of the second aspect of the invention provides a1-aryl-5-alkyl pyrazoles of formula (I) wherein:

-   -   R₁ is hydrogen, cyano, fluoro, chloro, R₈, formyl, —C(O)R₈,        —C(O)OR₈, —C(O)NR₉R₁₀, or —C(S)NH₂;    -   R₂ is C₁-C₂ alkyl, C₁-C₂ fluoroalkyl, C₁-C₂ chloroalkyl, or        —S(O)_(m)R₁₁;    -   R₃ is methyl or ethyl,    -   R₄, R₅ and R₇ are independently selected from the group        consisting of hydrogen, fluoro, chloro, C₁-C₂alkyl,        C₁-C₂-fluoroalkyl, C₁-C₂-chloroalkyl, cyano and nitro;    -   R₆ is fluoro, chloro, C₁-C₂ alkyl, C₁-C₂ fluoroalkyl, C₁-C₂        chloroalkyl, C₁-C₂ alkoxy, C₁-C₂ fluoroalkyloxy, C₁-C₂        chloroalkyloxy, cyano, nitro, —C(O)R₁₂, —S(O)_(n)R₁₂ or SF₅;    -   Z is a nitrogen atom or C—R₁₃;    -   R₈ is C₁-C₂alkyl, C₁-C₂-fluoroalkyl or C₁-C₂-chloroalkyl;    -   R₉ is hydrogen, C₁-C₂alkyl, C₁-C₂-fluoroalkyl or        C₁-C₂-chloroalkyl;    -   R₁₀ is hydrogen, C₁-C₂ alkyl, C₁-C₂-fluoroalkyl or C₁-C₂        chloroalkyl;    -   R₁₁ is C₁-C₂alkyl, C₁-C₂-fluoroalkyl, C₁-C₂-chloroalkyl,        C₂-C₄alkenyl, C₂-C₄ fluoroalkenyl, C₂-C₄ chloroalkenyl, C₂-C₄        alkynyl, C₂-C₄ fluoroalkynyl or C₂-C₄ chloroalkynyl;    -   R₁₂ is C₁-C₂alkyl, C₁-C₂-fluoroalkyl or C₁-C₂-chloroalkyl;    -   R₁₃ is hydrogen, fluoro, chloro, cyano, nitro, C₁-C₂alkyl,        C₁-C₂-fluoroalkyl, C₁-C₂ chloroalkyl C₁-C₂ alkoxy, C₁-C₂        fluoroalkoxy or C₁-C₂ chloroalkoxy;    -   m is 0, 1 or 2; and    -   n is 0, 1 or 2; or    -   a salt thereof.

An embodiment of the second aspect of the invention, wherein Z is C—R₁₃,provides a 1-aryl-5-alkyl pyrazoles of formula (I) wherein

-   -   R₁ is cyano;    -   R₂ is —S(O)_(m)R₁₁;    -   R₃ is methyl or ethyl,    -   R₄, R₅, R₇ are independently hydrogen or halogen;    -   R₆ is C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy or SF₅; R₁₁ is C₁-C₄        haloalkyl;    -   R₁₃ is C₁-C₄ alkyl optionally substituted with one or more        fluoro or chloro or halogen; and    -   m is 0, 1 or 2; or    -   a salt thereof.

Another embodiment of the second aspect of the invention, wherein Z isC—R₁₃, provides a 1-aryl-5-alkyl pyrazoles of formula (I) wherein:

-   -   R₁ is cyano;    -   R₂ is —S(O)_(m)R₁₁;    -   R₃ is methyl or ethyl;    -   R₄, R₅, and R₇ are independently hydrogen or halogen;    -   R₆ is —CF₃, —OCF₃ or —SF₅;    -   R₁₁ is —CF₃, —CClF₂ or —CCl₂F;    -   R₁₃ is methyl, chloro or fluoro; and    -   m is 0, 1 or 2; or    -   a salt thereof.

Another embodiment of the second aspect of the invention wherein Z isC—R₁₃, provides a 1-aryl-5-alkyl pyrazoles of formula (I) wherein:

-   -   R₁ is cyano;    -   R₂ is —S(O)_(m)R₁₁;    -   R₃ is methyl or ethyl;    -   R₄ is hydrogen, Cl or F;    -   R₅ and R₇ are both hydrogen;    -   R₆ is —CF₃, —OCF₃ or —SF₅;    -   R₁₁ is —CF₃, —CClF₂ or —CCl₂F;    -   R₁₃ is methyl, chloro or fluoro; and    -   m is 0, 1 or 2; or    -   a salt thereof.

Another embodiment of the third aspect of the invention provides a1-aryl-5-alkyl pyrazole compound of formula (I) wherein:

-   -   R₃ is selected from the group consisting of C₁-C₄ haloalkyl,        C₁-C₄ alkyl substituted by one to three halogens, CH₂F and CHF₂;        and    -   R₁, R₂, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, m and n are        as defined above; or    -   a salt thereof.

Another embodiment of the third aspect of the invention provides a1-aryl-5-alkyl pyrazole compound of formula (I) wherein:

-   -   R₁ is hydrogen, cyano, halogen, R₈, formyl, —C(O)R₈, —C(O)OR₈,        —C(O)NR₉R₁₀, or —C(S)NH₂;    -   R₂ is alkyl, haloalkyl or —S(O)_(m)R₁₁,    -   R₃ is a C₁-C₄ haloalkyl,    -   R₄, R₅ and R₇ are independently hydrogen, halogen, alkyl,        haloalkyl, cyano or nitro;    -   R₆ is halogen, alkyl, haloalkyl, alkoxy, haloalkyloxy, cyano,        nitro, —C(O)R₁₂, —S(O)_(n)R₁₂ or —SF₅;    -   Z is a nitrogen atom or C—R₁₃;    -   R₈ is alkyl, haloalkyl, cycloalkyl or halocycloalkyl;    -   R₉ is hydrogen, alkyl, haloalkyl or alkoxy;    -   R₁₀ is hydrogen, alkyl, haloalkyl or alkoxy;    -   R₁₁ is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl or cycloalkyl;    -   R₁₂ is alkyl or haloalkyl;    -   R₁₃ is hydrogen, halogen, cyano, nitro, alkyl, haloalkyl, alkoxy        or haloalkoxy;    -   m is 0, 1 or 2; and    -   n is 0, 1 or 2; or    -   a salt thereof.

Another embodiment of the third aspect of the invention provides a1-aryl-5-alkyl pyrazoles of formula (I) wherein:

-   -   R₁ is hydrogen, cyano, halogen, R₈, formyl, —C(O)R₈, —C(O)OR₈,        —C(O)NR₉R₁₀, or —C(S)NH₂;    -   R₂ is C₁-C₄ alkyl, C₁-C₄ haloalkyl or —S(O)_(m)R₁₁,    -   R₃ is C₁-C₄ haloalkyl,    -   R₄, R₅ and R₇ are independently hydrogen, halogen, C₁-C₄ alkyl,        C₁-C₄ haloalkyl, cyano or nitro;    -   R₆ is halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄        haloalkyloxy, cyano, nitro, —C(O)R₁₂, —S(O)_(n)R₁₂ or SF₅;    -   Z is a nitrogen atom or C—R₁₃;    -   R₈ is C₁-C₄ alkyl, C₁-C₄ haloalkyl or cycloalkyl optionally        substituted with one or more halogens;    -   R₉ is hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl or C₁-C₄ alkoxy;    -   R₁₀ is hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl or C₁-C₄ alkoxy;    -   R₁₁ is C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₂-C₄ alkenyl, C₂-C₄        haloalkenyl, C₂-C₄ alkynyl, C₂-C₄ haloalkynyl or cycloalkyl;    -   R₁₂ is C₁-C₄ alkyl or C₁-C₄ haloalkyl;    -   R₁₃ is hydrogen, halogen, cyano, nitro, C₁-C₄ alkyl, C₁-C₄        haloalkyl, C₁-C₄ alkoxy or C₁-C₄ haloalkoxy;    -   m is 0, 1 or 2; and    -   n is 0, 1 or 2; or    -   a salt thereof.

Another embodiment of the third aspect of the invention provides a1-aryl-5-alkyl pyrazoles of formula (I) wherein:

-   -   R₁ is hydrogen, cyano, fluoro, chloro, R₈, formyl, —C(O)R₈,        —C(O)OR₈, —C(O)NR₉R₁₀, or —C(S)NH₂;    -   R₂ is C₁-C₂ alkyl, C₁-C₂ fluoroalkyl or —S(O)_(m)R₁₁;    -   R₃ is methyl or ethyl substituted with one to three halogens,    -   R₄, R₅ and R₇ are independently selected from the group        consisting of hydrogen, fluoro, chloro, C₁-C₂alkyl,        C₁-C₂-fluoroalkyl, C₁-C₂-chloroalkyl, cyano and nitro;    -   R₆ is fluoro, chloro, C₁-C₂alkyl, C₁-C₂-fluoroalkyl,        C₁-C₂-chloroalkyl, C₁-C₂alkoxy, C₁-C₂ fluoroalkyloxy, C₁-C₂        chloroalkyloxy, cyano, nitro, —C(O)R₁₂, —S(O)_(n)R₁₂ or SF₅;    -   Z is a nitrogen atom or C—R₁₃;    -   R₈ is C₁-C₂alkyl, C₁-C₂-fluoroalkyl or C₁-C₂-chloroalkyl;    -   R₉ is hydrogen, C₁-C₂ alkyl, C₁-C₂ fluoroalkyl or C₁-C₂        chloroalkyl;    -   R₁₀ is hydrogen, C₁-C₂alkyl, C₁-C₂ fluoroalkyl or C₁-C₂        chloroalkyl;    -   R₁₁ is C₁-C₂alkyl, C₁-C₂-fluoroalkyl, C₁-C₂-chloroalkyl,        C₂-C₄alkenyl, C₂-C₄ fluoroalkenyl, C₂-C₄ chloroalkenyl, C₂-C₄        alkynyl, C₂-C₄ fluoroalkynyl or C₂-C₄ chloroalkynyl;    -   R₁₂ is C₁-C₂alkyl, C₁-C₂-fluoroalkyl or C₁-C₂-chloroalkyl;    -   R₁₃ is hydrogen, fluoro, chloro, cyano, nitro, C₁-C₂alkyl,        C₁-C₂-fluoroalkyl, C₁-C₂ chloroalkyl C₁-C₂ alkoxy, C₁-C₂        fluoroalkoxy or C₁-C₂ chloroalkoxy;    -   m is 0, 1 or 2; and    -   n is 0, 1 or 2; or    -   a salt thereof.

Another embodiment of the third aspect of the invention, wherein Z isC—R₁₃, provides a 1-aryl-5-alkyl pyrazoles of formula (I) wherein

-   -   R₁ is cyano;    -   R₂ is —S(O)_(m)R₁₁;    -   R₃ is methyl or ethyl substituted with one to three halogens,    -   R₄, R₅, R₇ are independently hydrogen or halogen;    -   R₆ is C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy or SF₅;    -   R₁₁ is C₁-C₄ haloalkyl;    -   R₁₃ is C₁-C₄ alkyl or halogen; and    -   m is 0, 1 or 2; or    -   a salt thereof.

Another embodiment of the third aspect of the invention, wherein Z isC—R₁₃, provides a 1-aryl-5-alkyl pyrazoles of formula (I) wherein:

-   -   R₁ is cyano;    -   R₂ is —S(O)_(m)R₁₁;    -   R₃ is methyl or ethyl substituted with one to three halogens;    -   R₄, R₅, and R₇ are independently hydrogen or halogen;    -   R₆ is C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy or —SF₅;    -   R₁₁ is C₁-C₄ haloalkyl;    -   R₁₃ is C₁-C₄ alkyl or halogen; and    -   m is 0, 1 or 2; or    -   a salt thereof.

Another embodiment of the third aspect of the invention wherein Z isC—R₁₃, provides a 1-aryl-5-alkyl pyrazoles of formula (I) wherein:

-   -   R₁ is cyano;    -   R₂ is —S(O)_(m)R₁₁;    -   R₃ is —CH₂F, or —CHF₂;    -   R₄ is hydrogen, fluoro or chloro;    -   R₅ and R₇ are both hydrogen;    -   R₆ is —CF₃, —OCF₃ or SF₅;    -   R₁₁ is —CF₃, —CClF₂ or —CCl₂F;    -   R₁₃ is methyl, fluoro or chloro; and    -   m is 0, 1 or 2; or    -   a salt thereof.

Another embodiment of the third aspect of the invention wherein Z isC—R₁₃, provides a 1-aryl-5-alkyl pyrazoles of formula (I):

-   -   R₁ is cyano;    -   R₂ is —S(O)_(m)R₁₁;    -   R₃ is —CH₂F, or —CHF₂;    -   R₄ is Cl;    -   R₅ and R₇ are both hydrogen;    -   R₆ is —CF₃, —OCF₃ or —SF₅;    -   R₁₁ is —CF₃, —CClF₂ or —CCl₂F;    -   R₁₃ is chloro or fluoro; and    -   m is 0, 1 or 2; or    -   a salt thereof.

The invention also provides novel intermediate compounds (Ia) for theproduction of a 1-aryl-5-alkyl pyrazole compound of formula (Ia):

wherein:

-   -   R₁ is hydrogen, cyano, halogen, R₈, formyl, —C(O)R₈, —C(O)OR₈,        —C(O)NR₉R₁₀, or —C(S)NH₂;    -   R₂ is R₈ or —S(O)_(m)R₁₁,    -   R₃ is C₁-C₄ alkyl, substituted with at least one —OH;    -   R₄, R₅ and R₇ are independently hydrogen, halogen, alkyl,        haloalkyl, cyano or nitro;    -   R₆ is halogen, alkyl, haloalkyl, alkoxy, haloalkyloxy, cyano,        nitro, —C(O)R₁₂, —S(O)_(n)R₁₂ or SF₅;    -   Z is C—F;    -   R₈ is alkyl, haloalkyl, cycloalkyl or halocycloalkyl;    -   R₉ is hydrogen, alkyl or haloalkyl;    -   R₁₀ is hydrogen, alkyl or haloalkyl;    -   R₁₁ is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl or cycloalkyl;    -   R₁₂ is alkyl or haloalkyl;    -   m is 0, 1 or 2; and    -   n is 0, 1 or 2; or    -   a salt thereof.

Another embodiment of the 1-aryl-5-alkyl pyrazole compound of formula(Ia) is:

-   -   R₁ is hydrogen, cyano, halogen, R₈, formyl, —C(O)R₈, —C(O)OR₈,        —C(O)NR₉R₁₀, or —C(S)NH₂;    -   R₂ is R₈ or —S(O)_(m)R₁₁,    -   R₃ is C₁-C₄ alkyl, substituted with at least one —OH;    -   R₄, R₅ and R₇ are independently hydrogen, halogen, alkyl,        haloalkyl, cyano or nitro;    -   R₆ is halogen, alkyl, haloalkyl, alkoxy, haloalkyloxy, cyano,        nitro, —C(O)R₁₂, —S(O)_(n)R₁₂ or SF₅;    -   Z is a nitrogen atom or C—F;    -   R₈ is alkyl, haloalkyl, cycloalkyl or halocycloalkyl;    -   R₉ is hydrogen, alkyl or haloalkyl;    -   R₁₀ is hydrogen, alkyl or haloalkyl;    -   R₁₁ is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl or cycloalkyl;    -   R₁₂ is alkyl or haloalkyl;    -   m is 0, 1 or 2; and    -   n is 0, 1 or 2; or    -   a salt thereof.

Another embodiment of the 1-aryl-5-alkyl pyrazole compound of formula(Ia) is:

-   -   R₁ is hydrogen, cyano, halogen, R₈, formyl, —C(O)R₈, —C(O)OR₈,        —C(O)NR₉R₁₀, or —C(S)NH₂;    -   R₂ is alkyl, haloalkyl or, —S(O)_(m)R₁₁, or cycloalkyl    -   R₃ is C₁-C₄ alkyl, substituted with at least one —OH;    -   R₄, R₅ and R₇ are independently hydrogen, halogen, alkyl,        haloalkyl, alkoxy, cyano or nitro;    -   R₆ is halogen, alkyl, haloalkyl, alkoxy, haloalkyloxy, cyano,        nitro, —C(O)R₁₂, —S(O)_(n)R₁₂ or SF₅;    -   Z is C—F;    -   R₈ is alkyl, haloalkyl, cycloalkyl or halocycloalkyl;    -   R₉ is hydrogen, alkyl or haloalkyl;    -   R₁₀ is hydrogen, alkyl or haloalkyl;    -   R₁₁ is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl or cycloalkyl;    -   R₁₂ is alkyl or haloalkyl;    -   m is 0, 1 or 2; and    -   n is 0, 1 or 2; or    -   a salt thereof.

Another embodiment of the invention provides 1-aryl-5-alkyl pyrazoles offormula (I) wherein:

-   -   R₁ is hydrogen, cyano, halogen, R₈, formyl, —C(O)R₈, —C(O)OR₈,        —C(O)NR₉R₁₀, or —C(S)NH₂;    -   R₂ is C₁-C₄ alkyl, C₁-C₄ haloalkyl, or —S(O)_(m)R₁₁,    -   R₃ is a C₁-C₄ alkyl, substituted with an —OH;    -   R₄, R₅ and R₇ are independently hydrogen, halogen, C₁-C₄ alkyl,        C₁-C₄ haloalkyl, cyano or nitro;    -   R₆ is halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄        haloalkyloxy, cyano, nitro, —C(O)R₁₂, —S(O)_(n)R₁₂ or SF₅;    -   Z is C—F;    -   R₈ is C₁-C₄ alkyl, C₁-C₄ haloalkyl or cycloalkyl optionally        substituted with one or more halogens;    -   R₉ is hydrogen, C₁-C₄ alkyl or C₁-C₄ haloalkyl;    -   R₁₀ is hydrogen, C₁-C₄ alkyl or C₁-C₄ haloalkyl;    -   R₁₁ is C₁-C₄alkyl, C₁-C₄haloalkyl, C₂-C₄alkenyl,        C₂-C₄haloalkenyl, C₂-C₄alkynyl, C₂-C₄ haloalkynyl or cycloalkyl;    -   R₁₂ is C₁-C₄ alkyl or C₁-C₄ haloalkyl;    -   m is 0, 1 or 2; and    -   n is 0, 1 or 2; or    -   a salt thereof.

Another embodiment of the invention provides 1-aryl-5-alkyl pyrazoles offormula (I) wherein:

-   -   R₁ is hydrogen, cyano, fluoro, chloro, R₈, formyl, —C(O)R₈,        —C(O)OR₈, —C(O)NR₉R₁₀, or —C(S)NH₂;    -   R₂ is C₁-C₂ alkyl, C₁-C₂ fluoroalkyl or —S(O)_(m)R₁₁;    -   R₃ is C₁-C₄ alkyl, substituted with an —OH;    -   R₄, R₅ and R₇ are independently selected from the group        consisting of hydrogen, fluoro, chloro, C₁-C₂ alkyl, C₁-C₂        fluoroalkyl, C₁-C₂ chloroalkyl, C₁-C₂ alkoxy, C₁-C₂        fluoroalkoxy, C₁-C₂-chloroalkoxy, C₁-C₂alkylthio,        C₁-C₂-fluoroalkylthio, C₁-C₂ chloroalkylthio, cyano and nitro;    -   R₆ is fluoro, chloro, C₁-C₂alkyl, C₁-C₂-fluoroalkyl,        C₁-C₂-chloroalkyl, C₁-C₂alkoxy, C₁-C₂-fluoroalkyloxy, C₁-C₂        chloroalkyloxy, cyano, nitro, —C(O)R₁₂, —S(O)_(n)R₁₂ or SF₅;    -   Z is C—F;    -   R₈ is C₁-C₂alkyl, C₁-C₂-fluoroalkyl or C₁-C₂-chloroalkyl;    -   R₉ is hydrogen, C₁-C₂alkyl, C₁-C₂-fluoroalkyl or        C₁-C₂-chloroalkyl;    -   R₁₀ is hydrogen, C₁-C₂alkyl, C₁-C₂-fluoroalkyl or        C₁-C₂-chloroalkyl;    -   R₁₁ is C₁-C₂alkyl, C₁-C₂-fluoroalkyl, C₁-C₂-chloroalkyl,        C₂-C₄alkenyl, C₂-C₄ fluoroalkenyl, C₂-C₄ chloroalkenyl, C₂-C₄        alkynyl, C₂-C₄ fluoroalkynyl or C₂-C₄ chloroalkynyl;    -   R₁₂ is C₁-C₂alkyl, C₁-C₂-fluoroalkyl or C₁-C₂-chloroalkyl;    -   m is 0, 1 or 2; and    -   n is 0, 1 or 2; or    -   a salt thereof.        Compositions

Also contemplated within the scope of the invention are acid or basesalts, where applicable, of the 1-aryl-5-alkyl-pyrazoles provided forherein.

The term “acid” contemplates all pharmaceutically, veterinary oragriculturally acceptable inorganic or organic acids. Inorganic acidsinclude mineral acids such as hydrohalic acids, such as hydrobromic andhydrochloric acids, sulfuric acids, phosphoric acids and nitric acids.Organic acids include all pharmaceutically acceptable aliphatic,alicyclic and aromatic carboxylic acids, dicarboxylic acidstricarboxylic acids and fatty acids. In one embodiment of the acids, theacids are straight chain or branched, saturated or unsaturated C₁-C₂₀aliphatic carboxylic acids, which are optionally substituted by halogenor by hydroxyl groups, or C₆-C₁₂ aromatic carboxylic acids. Examples ofsuch acids are carbonic acid, formic acid, fumaric acid, acetic acid,propionic acid, isopropionic acid, valeric acid, α-hydroxy acids, suchas glycolic acid and lactic acid, chloroacetic acid, benzoic acid,methane sulfonic acid, and salicylic acid. Examples of dicarboxylicacids include oxalic acid, malic acid, succinic acid, tataric acid andmaleic acid. An example of a tricarboxylic acid is citric acid. Fattyacids include all pharmaceutically or veterinary acceptable saturated orunsaturated aliphatic or aromatic carboxylic acids having 4 to 24 carbonatoms. Examples include butyric acid, isobutyric acid, sec-butyric acid,lauric acid, palmitic acid, stearic acid, oleic acid, linoleic acid,linolenic acid, and phenylsteric acid. Other acids include gluconicacid, glycoheptonic acid and lactobionic acid.

The term “base” contemplates all pharmaceutically, veterinary oragriculturally acceptable inorganic or organic bases. Such basesinclude, for example, the alkali metal and alkaline earth metal salts,such as the lithium, sodium, potassium, magnesium or calcium salts.Organic bases include the common hydrocarbyl and heterocyclic aminesalts, which include, for example, the morpholine and piperidine salts.

Ectoparasiticidal compositions of the invention comprise a1-aryl-5-alkyl pyrazole and an acceptable carrier, for example aveterinarily acceptable carrier or an ectoparasiticidally acceptablecarrier. In one embodiment of the invention, the ectoparasiticidallyacceptable carrier is an organic solvent commonly used in theformulation art. These organic solvents may be found, for example, inRemington Pharmaceutical Science, 16^(th) Edition (1986). These solventsinclude, for example, acetone, ethyl acetate, methanol, ethanol,isopropanol, dimethylformamide, dichloromethane or diethylene glycolmonoethyl ether (Transcutol). These solvents can be supplemented byvarious excipients according to the nature of the desired phases, suchas C₈-C₁₀ caprylic/capric triglyceride (Estasan or Miglyol 812), oleicacid or propylene glycol.

Pesticidal compositions of the invention comprise a 1-aryl-5-alkylpyrazole and an acceptable carrier, for example a agriculturallyacceptable carrier. In one embodiment of the invention, theagriculturally acceptable carrier is an organic solvent commonly used inthe formulation art. These organic solvents may be found, for example,in C. Marsden, “Solvents Guide”, 2nd Ed., Interscience, N.Y. 1963. Thesesolvents include, for example, acetone, butanol, cyclohexanone,dimethylformamide, xylene or else higher-boiling aromatics orhydrocarbons or mixtures of these. These solvents can be supplemented byvarious ionic and/or nonionic surfactants (emulsifiers).

Formulations and Administration for Pharmaceutical/Veterinary Use

The composition of the invention can also be in a variety of forms whichinclude, but are not limited to, oral formulations, injectableformulations, and topical, dermal or subdermal formulations.

The composition of the invention may be in a form suitable for oral use,for example, as baits (see, e.g., U.S. Pat. No. 4,564,631), dietarysupplements, troches, lozenges, chewables, tablets, hard or softcapsules, emulsions, aqueous or oily suspensions, aqueous or oilysolutions, oral drench formulations, dispersible powders or granules,syrups or elixirs, enteric formulations or pastes. Compositions intendedfor oral use may be prepared according to any method known in the artfor the manufacture of pharmaceutical compositions and such compositionsmay contain one or more agents selected from the group consisting ofsweetening agents, bittering agents, flavoring agents, coloring agentsand preserving agents in order to provide pharmaceutically elegant andpalatable preparations.

Tablets may contain the active ingredient in admixture with non-toxic,pharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example,magnesium stearate, stearic acid or talc, the tablets may be uncoated orthey may be coated by known techniques to delay disintegration andabsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period. For example, a time delay material such asglyceryl monostearate or glyceryl distearate may be employed. They mayalso be coated by the technique described in U.S. Pat. Nos. 4,256,108;4,166,452; and 4,265,874 (incorporated herein by reference) to formosmotic therapeutic tablets for controlled release.

Formulations for oral use may be hard gelatin capsules, wherein theactive ingredient is mixed with an inert solid diluent, for example,calcium carbonate, calcium phosphate or kaolin. Capsules may also besoft gelatin capsules, wherein the active ingredient is mixed with wateror miscible solvents such as propylene glycol, PEGs and ethanol, or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

The compositions of the invention may also be in the form ofoil-in-water or water-in-oil emulsions. The oily phase maybe a vegetableoil, for example, olive oil or arachis oil, or a mineral oil, forexample, liquid paraffin or mixtures of these. Suitable emulsifyingagents may be naturally-occurring phosphatides, for example, soy bean,lecithin, and esters or partial esters derived from fatty acids andhexitol anhydrides, for example, sorbitan monoleate, and condensationproducts of the said partial esters with ethylene oxide, for example,polyoxyethylene sorbitan monooleate. The emulsions may also containsweetening agents, bittering agents, flavoring agents, and/orpreservatives.

In one embodiment of the formulation, the composition of the inventionis in the form of a microemulsion. Microemulsions are well suited as theliquid carrier vehicle. Microemulsions are quaternary systems comprisingan aqueous phase, an oily phase, a surfactant and a cosurfactant. Theyare translucent and isotropic liquids.

Microemulsions are composed of stable dispersions of microdroplets ofthe aqueous phase in the oily phase or conversely of microdroplets ofthe oily phase in the aqueous phase. The size of these microdroplets isless than 200 nm (1000 to 100,000 nm for emulsions). The interfacialfilm is composed of an alternation of surface-active (SA) andco-surface-active (Co-SA) molecules which, by lowering the interfacialtension, allows the microemulsion to be formed spontaneously.

In one embodiment of the oily phase, the oily phase can be formed frommineral or vegetable oils, from unsaturated polyglycosylated glyceridesor from triglycerides, or alternatively from mixtures of such compounds.In one embodiment of the oily phase, the oily phase comprises oftriglycerides; in another embodiment of the oily phase, thetriglycerides are medium-chain triglycerides, for example C₈-C₁₀caprylic/capric triglyceride. In another embodiment of the oily phasewill represent a % v/v range selected from the group consisting of about2 to about 15%; about 7 to about 10%; and about 8 to about 9% v/v of themicroemulsion.

The aqueous phase includes, for example water or glycol derivatives,such as propylene glycol, glycol ethers, polyethylene glycols orglycerol. In one embodiment of the glycol derivatives, the glycol isselected from the group consisting of propylene glycol, diethyleneglycol monoethyl ether, dipropylene glycol monoethyl ether and mixturesthereof. Generally, the aqueous phase will represent a proportion fromabout 1 to about 4% v/v in the microemulsion.

Surfactants for the microemulsion include diethylene glycol monoethylether, dipropyelene glycol monomethyl ether, polyglycolyzed C₈-C₁₀glycerides or polyglyceryl-6 dioleate. In addition to these surfactants,the cosurfactants include short-chain alcohols, such as ethanol andpropanol.

Some compounds are common to the three components discussed above, i.e.,aqueous phase, surfactant and cosurfactant. However, it is well withinthe skill level of the practitioner to use different compounds for eachcomponent of the same formulation. In one embodiment for the amount ofsurfactant/cosurfactant, the cosurfactant to surfactant ratio will befrom about 1/7 to about 1/2. In another embodiment for the amount ofcosurfactant, there will be from about 25 to about 75% v/v of surfactantand from about 10 to about 55% v/v of cosurfactant in the microemulsion.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example, atachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example, beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as sucrose, saccharinor aspartame, bittering agents, and flavoring agents may be added toprovide a palatable oral preparation. These compositions may bepreserved by the addition of an anti-oxidant such as ascorbic acid, orother known preservatives.

Aqueous suspensions may contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example, sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample, heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide, with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agentsand/or bittering agents, such as those set forth above.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example, sweetening, bittering, flavoring andcoloring agents, may also be present.

Syrups and elixirs may be formulated with sweetening agents, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative, flavoringagent(s) and/or coloring agent(s).

In another embodiment of the invention, the composition can be in pasteform. Examples of embodiments in a paste form include but are notlimited to those described in U.S. Pat. Nos. 6,787,342 and 7,001,889(each of which are incorporated herein by reference). In addition to the1-aryl-5-alkyl pyrazole compound of the invention, the paste can alsocontain fumed silica; a viscosity modifier; a carrier; optionally, anabsorbent; and optionally, a colorant, stabilizer, surfactant, orpreservative.

The process for preparing a paste formulation comprises the steps of:

(a) dissolving or dispersing the 1-aryl-5-alkyl compound into thecarrier by mixing;

(b) adding the fumed silica to the carrier containing the dissolved1-aryl-5-alkyl pyrazole compound and mixing until the silica isdispersed in the carrier;

(c) allowing the intermediate formed in (b) to settle for a timesufficient in order to allow the air entrapped during step (b) toescape; and

(d) adding the viscosity modifier to the intermediate with mixing toproduce a uniform paste.

The above steps are illustrative, but not limiting. For example, step(a) can be the last step.

In one embodiment of the formulation, the formulation is a pastecontaining 1-aryl-5-alkyl pyrazole compound, fumed silica, a viscositymodifier, an absorbent, a colorant; and a hydrophilic carrier which istriacetin, a monoglyceride, a diglyceride, or a triglyceride.

The paste may also include, but is not limited to, a viscosity modifierselected from the group consisting of PEG 200, PEG 300, PEG 400, PEG600, monoethanolamine, triethanolamine, glycerol, propylene glycol,polyoxyethylene (20) sorbitan mono-oleate (polysorbate 80 or Tween 80),and polyoxamers (e.g., Pluronic L 81); an absorbent selected from thegroup consisting of magnesium carbonate, calcium carbonate, starch, andcellulose and its derivatives; and a colorant selected from the groupconsisting of titanium dioxide iron oxide, and FD&C Blue #1 AluminumLake.

The compositions may be in the form of a sterile injectable aqueous oroleagenous suspension. This suspension may be formulated according tothe known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example, as a solution in 1,3-butane diol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solutionand isotonic sodium chloride solution. Cosolvents such as ethanol,propylene glycol or polyethylene glycols may also be used.Preservatives, such as phenol or benzyl alcohol, may be used.

In addition, sterile, fixed oils are conventionally employed as asolvent or suspending medium. For this purpose any bland fixed oil maybe employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

Topical, dermal and subdermal formulations can include emulsions,creams, ointments, gels, pastes, powders, shampoos, pour-onformulations, ready-to-use formulations, spot-on solutions andsuspensions. Topical application of an inventive compound or of acomposition including at least one inventive compound among activeagent(s) therein, a spot-on composition, can allow for the inventivecompound to be distributed through the glands (e.g. sebaceous glands) ofthe animal and/or allow active agent(s) to achieve a systemic effect(plasma concentration) or throughout the haircoat. When the compound isdistributed throughout glands, the glands can act as a reservoir,whereby there can be a long-lasting, e.g. 1-2 months effect. Spot-onformulations are typically applied in a localized region which refers toan area other than the entire animal. In one embodiment of a localizedregion, the location is between the shoulders. In another embodiment ofa localized region is a stripe, e.g. a stripe from head to tail of theanimal.

Pour-on formulations are described in U.S. Pat. No. 6,010,710,incorporated herein by reference. The pour-on formulations areadvantageously oily, and generally comprise a diluent or vehicle andalso a solvent (e.g. an organic solvent) for the active ingredient ifthe latter is not soluble in the diluent.

Organic solvents that can be used in the invention include but are notlimited to: acetyltributyl citrate, fatty acid esters such as thedimethyl ester, diisobutyl adipate, acetone, acetonitrile, benzylalcohol, butyl diglycol, dimethylacetamide, dimethylformamide,dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol,ethylene glycol monoethyl ether, ethylene glycol monomethyl ether,monomethylacetamide, dipropylene glycol monomethyl ether, liquidpolyoxyethylene glycols, propylene glycol, 2-pyrrolidone (e.g.N-methylpyrrolidone), diethylene glycol monoethyl ether, ethylene glycoland diethyl phthalate, or a mixture of at least two of these solvents.

As vehicle or diluent, mention may be made of plant oils such as, butnot limited to soybean oil, groundnut oil, castor oil, corn oil, cottonoil, olive oil, grape seed oil, sunflower oil, etc.; mineral oils suchas, but not limited to, petrolatum, paraffin, silicone, etc.; aliphaticor cyclic hydrocarbons or alternatively, for example, medium-chain (suchas C8 to C12) triglycerides.

In another embodiment of the invention, an emollient and/or spreadingand/or film-forming agent will be added. One embodiment of the emollientand/or spreading and/or film-forming agent are those agents selectedfrom the group consisting of:

(a) polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinylacetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol,mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan esters;lecithin, sodium carboxymethylcellulose, silicone oils,polydiorganosiloxane oils (such as polydimethylsiloxane (PDMS) oils),for example those containing silanol functionalities, or a 45V2 oil,

(b) anionic surfactants such as alkaline stearates, sodium, potassium orammonium stearates; calcium stearate, triethanolamine stearate; sodiumabietate; alkyl sulphates (e.g. sodium lauryl sulphate and sodium cetylsulphate); sodium dodecylbenzenesulphonate, sodiumdioctylsulphosuccinate; fatty acids (e.g. those derived from coconutoil),

(c) cationic surfactants such as water-soluble quaternary ammonium saltsof formula N⁺R′R″R′″R″″, Y in which the radicals R are optionallyhydroxylated hydrocarbon radicals and Y is an anion of a strong acidsuch as the halide, sulphate and sulphonate anions;cetyltrimethylammonium bromide is among the cationic surfactants whichcan be used,

(d) amine salts of formula N⁺R′R″R′″ in which the radicals R areoptionally hydroxylated hydrocarbon radicals; octadecylaminehydrochloride is among the cationic surfactants which can be used,

(e) nonionic surfactants such as sorbitan esters, which are optionallypolyoxyethylenated (e.g. polysorbate 80), polyoxyethylenated alkylethers; polyoxypropylated fatty alcohols such as polyoxypropylene-styrolether; polyethylene glycol stearate, polyoxyethylenated derivatives ofcastor oil, polyglycerol esters, polyoxyethylenated fatty alcohols,polyoxyethylenated fatty acids, copolymers of ethylene oxide andpropylene oxide,

(f) amphoteric surfactants such as the substituted lauryl compounds ofbetaine; or

(g) a mixture of at least two of these agents.

The solvent will be used in proportion with the concentration of the1-aryl-5-alkyl pyrazole compound and its solubility in this solvent. Itwill be sought to have the lowest possible volume. The vehicle makes upthe difference to 100%.

In one embodiment of the amount of emollient, the emollient is used in aproportion selected from the group consisting of from 0.1 to 10% and0.25 to 5%, by volume.

In another embodiment of the invention, the composition can be inready-to-use solution form as is described in U.S. Pat. No. 6,395,765,incorporated herein by reference. In addition to the 1-aryl-5-alkylpyrazole compound, the ready-to-use solution can contain acrystallization inhibitor, an organic solvent and an organic co-solvent.

In one embodiment of the amount of crystallization inhibitor, thecrystallization inhibitor can be present in a proportion selected fromthe group consisting of about 1 to about 20% (w/v) and about 5 to about15%. In another embodiment of the amount of crystallization inhibitor,the amount corresponds to the test in which 0.3 ml of a solutioncomprising 10% (w/v) of 1-aryl-5-alkyl pyrazole compound in the liquidcarrier and 10% of the inhibitor are deposited on a glass slide at 20°C. and allowed to stand for 24 hours. The slide is then observed withthe naked eye. Acceptable inhibitors are those whose addition providesfor few (e.g. less than ten crystals) or no crystal.

The organic solvent has a dielectric constant of a range selected fromthe group consisting of between about 10 and 35 and between about 20 and30, the content of this organic solvent in the overall compositionrepresenting the complement to 100% of the composition; and the organicco-solvent having a boiling point selected from the ranges consisting ofbelow 100° C., and below 80° C., and having a dielectric constant of arange selected from the group consisting of between about 10 and 40 andbetween about 20 and 30; this co-solvent may be present in thecomposition in a organic co-solvent/organic solvent weight/weight (W/W)ratio of between about 1/15 and 1/2. The solvent is volatile so as toact as a drying promoter, and is miscible with water and/or with theorganic solvent.

The formulation can also comprise an antioxidizing agent intended toinhibit oxidation in air, this agent being present in a proportionselected from a range consisting of about 0.005 to about 1% (w/v) andabout 0.01 to about 0.05%.

Crystallization inhibitors which are useful for the invention includebut are not limited to:

-   (a) polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl    acetate and of vinylpyrrolidone, polyethylene glycols, benzyl    alcohol, mannitol, glycerol, sorbitol or polyoxyethylenated esters    of sorbitan; lecithin or sodium carboxymethylcellulose; or acrylic    derivatives, such as methacrylates and others;-   (b) anionic surfactants, such as alkaline stearates (e.g. sodium,    potassium or ammonium stearate); calcium stearate or triethanolamine    stearate; sodium abietate; alkyl sulphates, which include but are    not limited to sodium lauryl sulphate and sodium cetyl sulphate;    sodium dodecylbenzenesulphonate or sodium dioctyl sulphosuccinate;    or fatty acids (e.g. coconut oil);-   (c) cationic surfactants, such as water-soluble quaternary ammonium    salts of formula N⁺R′R″R′″R″″Y⁻, in which the R radicals are    identical or different optionally hydroxylated hydrocarbon radicals    and Y⁻ is an anion of a strong acid, such as halide, sulphate and    sulphonate anions; cetyltrimethylammonium bromide is one of the    cationic surfactants which can be used;-   (d) amine salts of formula N⁺R′R″R′″, in which the R radicals are    identical or different optionally hydroxylated hydrocarbon radicals;    octadecylamine hydrochloride is one of the cationic surfactants    which can be used;-   (e) non-ionic surfactants, such as optionally polyoxyethylenated    esters of sorbitan, e.g. Polysorbate 80, or polyoxyethylenated alkyl    ethers; polyethylene glycol stearate, polyoxyethylenated derivatives    of castor oil, polyglycerol esters, polyoxyethylenated fatty    alcohols, polyoxyethylenated fatty acids or copolymers of ethylene    oxide and of propylene oxide;-   (f) amphoteric surfactants, such as substituted lauryl compounds of    betaine; or-   (g) a mixture of at least two of the compounds listed in (a)-(f)    above.

In one embodiment of the crystallization inhibitor, a crystallizationinhibitor pair will be used. Such pairs include, for example, thecombination of a film-forming agent of polymeric type and of asurface-active agent. These agents will be selected from the compoundsmentioned above as crystallization inhibitor.

In one embodiment of the film-forming agent, the agents are of thepolymeric type which include but are not limited to the various gradesof polyvinylpyrrolidone, polyvinyl alcohols, and copolymers of vinylacetate and of vinylpyrrolidone.

In one embodiment of the surface-active agents, the agents include butare not limited to those made of non-ionic surfactants; in anotherembodiment of the surface active agents, the agent is apolyoxyethylenated esters of sorbitan and in yet another embodiment ofthe surface-active agent, the agents include the various grades ofpolysorbate, for example Polysorbate 80.

In another embodiment of the invention, the film-forming agent and thesurface-active agent can be incorporated in similar or identical amountswithin the limit of the total amounts of crystallization inhibitormentioned elsewhere.

The pair thus constituted secures, in a noteworthy way, the objectivesof absence of crystallization on the coat and of maintenance of thecosmetic appearance of the skin or fur, that is to say without atendency towards sticking or towards a sticky appearance, despite thehigh concentration of active material.

In one embodiment of the antioxidizing agents, the agents are thoseconventional in the art and include but is not limited to butylatedhydroxyanisole, butylated hydroxytoluene, ascorbic acid, sodiummetabisulphite, propyl gallate, sodium thiosulphate or a mixture of notmore than two of them.

The formulation adjuvants discussed above are well known to thepractitioner in this art and may be obtained commercially or throughknown techniques. These concentrated compositions are generally preparedby simple mixing of the constituents as defined above; advantageously,the starting point is to mix the active material in the main solvent andthen the other ingredients or adjuvants are added.

The volume applied can be of the order of about 0.3 to about 1 ml. Inone embodiment for the volume, the volume is on the order of about 0.5ml, for cats and on the order of about 0.3 to about 3 ml for dogs,depending on the weight of the animal.

In another embodiment of the invention, application of a spot-onformulation according to the present invention can also providelong-lasting and broad-spectrum efficacy when the solution is applied tothe mammal or bird. The spot-on formulations provide for topicaladministration of a concentrated solution, suspension, microemulsion oremulsion for intermittent application to a spot on the animal, generallybetween the two shoulders (solution of spot-on type).

For spot-on formulations, the carrier can be a liquid carrier vehicle asdescribed in U.S. Pat. No. 6,426,333 (incorporated herein by reference),which in one embodiment of the spot-on formulation comprises a solventand a cosolvent wherein the solvent is selected from the groupconsisting of acetone, acetonitrile, benzyl alcohol, butyl diglycol,dimethylacetamide, dimethylformamide, dipropylene glycol n-butyl ether,ethanol, isopropanol, methanol, ethylene glycol monoethyl ether,ethylene glycol monomethyl ether, monomethylacetamide, dipropyleneglycol monomethyl ether, liquid polyoxyethylene glycols, propyleneglycol, 2-pyrrolidone (e.g. N-methylpyrrolidone), diethylene glycolmonoethyl ether, ethylene glycol, diethyl phthalate fatty acid esters,such as the diethyl ester or diisobutyl adipate, and a mixture of atleast two of these solvents and the cosolvent is selected from the groupconsisting of absolute ethanol, isopropanol or methanol.

The liquid carrier vehicle can optionally contain a crystallizationinhibitor selected from the group consisting of an anionic surfactant, acationic surfactant, a non-ionic surfactant, an amine salt, anamphoteric surfactant or polyvinylpyrrolidone, polyvinyl alcohols,copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycols,benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylenatedsorbitan esters; lecithin, sodium carboxymethylcellulose, and acrylicderivatives, or a mixture of these crystallization inhibitors.

Spot-on formulations may be prepared by dissolving the activeingredients into the pharmaceutically or veterinary acceptable vehicle.Alternatively, the spot-on formulation can be prepared by encapsulationof the active ingredient to leave a residue of the therapeutic agent onthe surface of the animal. These formulations will vary with regard tothe weight of the therapeutic agent in the combination depending on thespecies of host animal to be treated, the severity and type of infectionand the body weight of the host.

Dosage forms may contain from about 0.5 mg to about 5 g of an activeagent. In one embodiment of the dosage form, the dosage is from about 1mg to about 500 mg of an active agent, typically about 25 mg, about 50mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500mg, about 600 mg, about 800 mg, or about 1000 mg.

In one embodiment of the invention, the active agent is present in theformulation at a concentration of about 0.05 to 10% weight/volume. Inanother embodiment of the invention, the active agent is present in theformulation as a concentration from about 0.1 to 2% weight/volume. Inyet another embodiment of the invention, the active agent is present inthe formulation as a concentration from about 0.25 to about 1.5%weight/volume. In still another embodiment of the invention, the activeagent is present in the formulation as a concentration about 1%weight/volume.

Formulations and Administration for Agrochemical Use

The compounds of the formula (I) or their salts can be employed as suchor in the form of their preparations (formulations) alone or ascombinations with other pesticidally active substances, such as, forexample, insecticides, attractants, sterilants, acaricides, nematicides,herbicides, fungicides, and with safeners, fertilizers and/or growthregulators, for example as a premix/readymix.

The insecticides include, for example, phosphoric esters, carbamates,carboxylic esters, chlorinated hydrocarbons, phenylureas, substancesprepared by microorganisms.

Examples of insecticides which may optionally be admixed include but arenot limited to:

phosphoric esters, such as azinphos-ethyl, azinphos-methyl,a-1(4-chlorophenyl)-4-(O-ethyl, S-propyl)phosphoryloxy-pyrazole,chlorpyrifos, coumaphos, demeton, demeton-S-methyl, diazinon,dichlorvos, dimethoate, ethoate, ethoprophos, etrimfos, fenitrothion,fenthion, heptenophas, parathion, parathion-methyl, phosalone, poxim,pirimiphos-ethyl, pirimiphos-methyl, profenofos, prothiofos, sulfprofos,triazophos and trichlorphon;

carbamates, such as aldicarb, bendiocarb, a-2-(1-methylpropyl)-phenylmethylcarbamate, butocarboxim, butoxycarboxim, carbaryl, carbofuran,carbosulfan, cloethocarb, isoprocarb, methomyl, oxamyl, pirimicarb,promecarb, propoxur and thiodicarb;

organosilicon compounds (e.g. dimethyl(phenyl)silyl-methyl3-phenoxybenzyl ethers, such as dimethyl-(4-ethoxyphenyl)-silylmethyl3-phenoxybenzyl ether) or (dimethylphenyl)-silyl-methyl2-phenoxy-6-pyridylmethyl ethers such as, for example,dimethyl-(9-ethoxy-phenyl)-silylmethyl 2-phenoxy-6-pyridylmethyl etheror [(phenyl)-3-(3-phenoxyphenyl)-propyl[(dimethyl)-silanes such as, forexample,(4-ethoxyphen-yl)-[3-(4-fluoro-3-phenoxyphenyl-propyl]dimethyl-silane,silafluofen;

pyrethroids (which are also useful for their repellent properties, e.g.against mosquitoes), such as allethrin, alphamethrin, bioresmethrin,byfenthrin, cycloprothrin, cyfluthirin, decamethrin, cyhalothrin,cypermethrin, deltamethrin, alpha-cyano-3-phenyl-2-methylbenzyl2,2-dimethyl-3-(2-chloro-2-trifluoro-methylvinyl)cyclopropane-carboxylate,fenpropathrin, fenfluthrin, fenvalerate, flucythrinate, flumethrin,fluvalinate, permethrin, resmethrin and tralomethrin;

nitroimines and nitromethylenes, such as1-[(6-chloro-3-pyridinyl)-methyl]-4,5-dihydro-N-nitro-1H-imidazole-2-amine(imidacloprid),N-[(6-chloro-3-pyridyl)-methyl]-N²-cyano-N¹-methylacetamide (NI-25);

abamectin, AC 303, 630 (chlorfenapyr), acephate, acrinathrin, alanycarb,aldoxycarb, aldrin, amitraz, azamethiphos, Bacillus thuringiensis,phosmet, phosphamidon, phosphine, prallethrin, propaphos, propetamphos,prothoate, pyraclofos, pyrethrins, pyridaben, pyridafenthion,pyriproxyfen, quinalphos, RH-7988, rotenone, sodium fluoride, sodiumhexafluorosilicate, sulfotep, sulfuryl fluoride, tar oils,teflubenzuron, tefluthrin, temephos, terbufos, tetrachlorvinphos,tetramethrin, O-2-tert-butyl-pyrimidin-5-yl-o-isopropylphosphorothiate,thiocyclam, thiofanox, thiometon, tralomethrin, triflumuron,trimethacarb, vamidothion, Verticillium Lacanii, XMC, xylylcarb,benfuracarb, bensultap, bifenthrin, bioallethrin, MERbioallethrin(S)-cyclopentenyl isomer, bromophos, bromophos-ethyl, buprofezin,cadusafos, calcium polysulphide, carbophenothion, cartap,quinomethionate, chlordane, chlorfenvinphos, chlorfluazuron,chlormephos, chloropicrin, chlorpyrifos, cyanophos, beta-cyfluthrin,alphacypermethrin, cyophenothrin, cyromazine, dazomet, DDT,demeton-S-methylsulphone, diafenthiuron, dialifos, dicrotophos,diflubenzuron, dinoseb, deoxabenzofos, diazacarb, disulfoton, DNOC,empenthrin, endosulfan, EPN, esfenvalerate, ethiofencarb, ethion,etofenprox, fenobucarb, fenoxycarb, fensulfothion, fipronil,flucycloxuron, flufenprox, flufenoxuron, fonofos, formetanate,formothion, fosmethilan, furathiocarb, heptachlor, hexaflumuron,hydramethylnon, hydrogen cyanide, hydroprene, IPSP, isazofos,isofenphos, isoprothiolane, isoxathion, iodfenphos, kadethrin, lindane,malathion, mecarbam, mephosfolan, mercurous chloride, metam,metarthizium, anisopliae, methacrifos, methamidophos, methidathion,methiocarb, methoprene, methoxychlor, methyl isothiocyanate, metholcarb,mevinphos, monocrotophos, naled, Neodiprion sertifer NPV, nicotine,omethoate, oxydemeton-methyl, pentachlorophenol, petroleum oils,phenothrin, phenthoate, phorate.

Other insecticides that may optionally be admixed may also be from theclass of the compounds described by U.S. Pat. No. 7,001,903.

Fungicides which may optionally be admixed are include but are notlimited to:

-   (1) Triazoles which include but are not limited to: azaconazole,    propiconazole, tebuconazole, cyproconazole, metconazole, amitrole,    azocyclotin, BAS 480F, bitertanol, difenoconazole, fenbuconazole,    fenchlorazole, fenethanil, fluquinconazole, flusilazole, flutriafol,    imibenconazole, isozofos, myclobutanil, paclobutrazol,    (±)-cis-1-(4-chlorophenyl)-2-(1H-1,2,4-triazol-1-yl)-cycloheptanol,    tetraconazole, triadimefon, triadimenol, triapenthenol,    triflumizole, triticonazole, uniconazole and their metal salts and    acid adducts.-   (2) Imidazoles which include but are not limited to: imazalil,    pefurazoate, prochloraz, triflumizole,    2-(1-tert-butyl)-1-(2-chlorophenyl)-3-(1,2,4-triazol-1-yl)-propan-2-ol,    thiazolecarboxanilides such as    2′,6′-dibromo-2-methyl-4-trifluoromethoxy-4′-trifluoromethyl-1,3-thiazole-5-carboxanilide,    1-imidazolyl-1-(4′-chlorophenoxy)-3,3-dimethylbutan-2-one and their    metal salts and acid adducts.-   (3) “Methyl (E)-2-phenyl-3-methoxyacrylate” compounds which include    but are not limited to: methyl    (E)-2-[2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl]3-methoxyacrylate,    methyl    (E)-2-[2-[6-(2-thioamidophenoxy)pyrimidin-4-yloxy]phenyl]-3-methoxyacrylate,    methyl    (E)-2-[2-[6-(2-fluorophenoxy)pyrimidin-4-yloxy]phenyl]-3-methoxyacrylate,    methyl    (E)-2-[2-[6-(2,6-difluorophenoxy)pyrimidin-4-yloxy]phenyl]-3-methoxyacrylate,    methyl    (E)-2-[2-[3-(pyrimidin-2-yloxy)phenoxy]phenyl]-3-methoxyacrylate,    methyl    (E)-2-[2-[3-(5-methylpyrimidin-2-yloxy)-phenoxy]phenyl]-3-methoxyacrylate,    methyl    (E)-2-[2-[3-(phenyl-sulphonyloxy)phenoxy]phenyl]-3-methoxyacrylate,    methyl    (E)-2-[2-[3-(4-nitrophenoxy)phenoxy]phenyl]-3-methoxyacrylate,    methyl (E)-2-[2-phenoxyphenyl]-3-methoxyacrylate, methyl    (E)-2-[2-(3,5-dimethyl-benzoyl)pyrrol-1-yl]-3-methoxyacrylate,    methyl (E)-2-[2-(3-methoxyphenoxy)phenyl]-3-methoxyacrylate, methyl    (E)-2[2-(2-phenylethen-1-yl)phenyl]-3-methoxyacrylate, methyl    (E)-2-[2-(3,5-dichlorophenoxy)pyridin-3-yl]-3-methoxyacrylate,    methyl    (E)-2-(2-(3-(1,1,2,2-tetrafluoroethoxy)phenoxy)phenyl)-3-methoxyacrylate,    methyl    (E)-2-(2-[3-(alpha-hydroxybenzyl)phenoxy]phenyl)-3-methoxyacrylate,    methyl (E)-2-(2-(4-phenoxypyridin-2-yloxy)phenyl)-3-methoxyacrylate,    methyl (E)-2-[2-(3-n-propyloxyphenoxy)phenyl]3-methoxyacrylate,    methyl (E)-2-[2-(3-isopropyloxyphenoxy)phenyl]-3-methoxyacrylate,    methyl    (E)-2-[2-[3-(2-fluorophenoxy)phenoxy]phenyl]-3-methoxyacrylate,    methyl (E)-2-[2-(3-ethoxyphenoxy)phenyl]-3-methoxyacrylate, methyl    (E)-2-[2-(4-tert-butyl-pyridin-2-yloxy)phenyl]-3-methoxyacrylate,    methyl    (E)-2-[2-[3-(3-cyanophenoxy)phenoxy]phenyl]-3-methoxyacrylate,    methyl    (E)-2-[2-[(3-methylpyridin-2-yloxymethyl)phenyl]-3-methoxyacrylate,    methyl    (E)-2-[2-[6-(2-methylphenoxy)pyrimidin-4-yloxy]phenyl]-3-methoxyacrylate,    methyl    (E)-2-[2-(5-bromo-pyridin-2-yloxymethyl)phenyl]-3-methoxyacrylate,    methyl    (E)-2-[2-(3-(3-iodopyridin-2-yloxy)phenoxy)phenyl]-3-methoxyacrylate,    methyl    (E)-2-[2-[6-(2-chloropyridin-3-yloxy)pyrimidin-4-yloxy]phenyl]-3-methoxyacrylate,    methyl    (E),(E)-2-[2-(5,6-di-methylpyrazin-2-ylmethyloximinomethyl)phenyl]-3-methoxyacrylate,    methyl    (E)-2-{2-[6-(6-methylpyridin-2-yloxy)pyrimidin-4-yloxy]phenyl}-3-methoxyacrylate,    methyl    (E),(E)-2-{2-(3-methoxyphenyl)methyloximinomethyl]-phenyl}-3-methoxyacrylate,    methyl    (E)-2-{2-(6-(2-azidophenoxy)-pyrimidin-4-yloxy]phenyl}-3-methoxyacrylate,    methyl    (E),(E)-2-{2-[6-phenylpyrimidin-4-yl)-methyloximinomethyl]phenyl}-3-methoxyacrylate,    methyl    (E),(E)-2-{2-[(4-chlorophenyl)-methyloximinomethyl]-phenyl}-3-methoxyacrylate,    methyl    (E)-2-{2-[6-(2-n-propylphenoxy)-1,3,5-triazin-4-yloxy]phenyl}-3-methoxyacrylate,    and methyl    (E),(E)-2-{2-[(3-nitrophenyl)methyloximinomethyl]phenyl}-3-methoxyacrylate;-   (4) Succinate Dehydrogenase Inhibitors which include but are not    limited to:    -   (a) fenfuram, furcarbanil, cyclafluramid, furmecyclox, seedvax,        metsulfovax, pyrocarbolid, oxycarboxin, shirlan, mebenil        (mepronil), benodanil, flutolanil (Moncut);    -   (b) naphthalene derivatives such as terbinafine, naftifine,        butenafine, 3-chloro-7-(2-aza-2,7,7-trimethyl-oct-3-en-5-ine);    -   (c) sulphenamides such as dichlofluanid, tolylfluanid, folpet,        fluorfolpet; captan, captofol;    -   (d) benzimidazoles such as carbendazim, benomyl, furathiocarb,        fuberidazole, thiophonatmethyl, thiabendazole or their salts;    -   (e) morpholine derivatives such as fenpropimorph, falimorph,        dimethomorph, dodemorph, aldimorph, fenpropidine and their        arylsulphonates, such as, for example, p-toluenesulphonic acid        and p-dodecylphenyl-sulphonic acid;    -   (f) dithiocarbamates, cufraneb, ferbam, mancopper, mancozeb,        maneb, metam, metiram, thiram zeneb, ziram;    -   (g) benzothiazoles, such as 2-mercaptobenzothiazole;    -   (h) benzamides, such as        2,6-dichloro-N-(4-trifluoromethylbenzyl)-benzamide;    -   (i) boron compounds, such as boric acid, boric esters, borax;    -   (j) formaldehyde and formaldehyde-releasing compounds, such as        benzyl alcohol mono-(poly)-hemiformal, oxazolidine,        hexa-hydro-S-triazines, N-methylolchloroacetamide,        paraformaldehyde, nitropyrin, oxolinic acid, tecloftalam;    -   (k) tris-N-(cyclohexyldiazeniumdioxy)-aluminium,        N-(cyclo-hexyldiazeniumdioxy)-tri-butyltin or K salts,        bis-N-(cyclohexyldiazeniumdioxy)-copper,        N-methylisothiazolin-3-one, 5-chloro-N-methylisothiazolin-3-one,        4,5-dichloro-N-octylisothiazolin-3-one,        N-octyl-isothiazolin-3-one, 4,5-trimethylene-isothiazolinone,        4,5-benzoisothiazolinone, N-methylolchloroacetamide;    -   (l) aldehydes, such as cinnamaldehyde, formaldehyde,        glutaraldehyde, β-bromo-cinnamaldehyde;    -   (m) thiocyanates, such as thiocyanatomethylthiobenzothiazole,        methylenebisthiocyanate, and the like;    -   (n) quaternary ammonium compounds, such as        benzyldimethyltetradecylammonium chloride,        benzyldimethyldodecylanmuonium chloride, didecyldimethylammonium        chloride;    -   (o) iodine derivatives, such as diiodomethyl p-tolyl sulphone,        3-iodo-2-propinyl alcohol, 4-chlorophenyl-3-iodopropargyl        formal, 3-bromo-2,3-diiodo-2-propenyl ethylcarbamate,        2,3,3-triiodoallyl alcohol, 3-bromo-2,3-diiodo-2-propenyl        alcohol, 3-iodo-2-propinyl n-butylcarbamate, 3-iodo-2-propinyl        n-hexylcarbamate, 3-iodo-2-propinyl cyclohexylcarbamate,        3-iodo-2-propinyl phenylcarbamate;    -   (p) phenol derivatives, such as tribromophenol,        tetrachlorophenol, 3-methyl-4-chlorophenol,        3,5-dimethyl-4-chlorophenol, phenoxyethanol, dichlorophene,        o-phenylphenol, m-phenylphenol, p-phenylphenol,        2-benzyl-4-chlorophenol and their alkali metal and alkaline        earth metal salts;    -   (q) microbicides having an activated halogen group, such as        chloroacetamide, bronopol, bronidox, tectamer, such as        2-bromo-2-nitro-1,3-propanediol, 2-bromo-4′-hydroxyacetophenone,        2,2-dibromo-3-nitrile-propionamide,        1,2-dibromo-2,4-dicyanobutane, β-bromo-β-nitrostyrene;    -   (r) pyridines, such as 1-hydroxy-2-pyridinethione (and their Na,        Fe, Mn, Zn salts), tetrachloro-4-methylsulphonylpyridine,        pyrimethanol, mepanipyrim, dipyrithion,        1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridine;    -   (s) metal soaps, such as tin naphthenate, copper naphthenate,        zinc naphthenate, tin octoate, copper octoate, zinc octoate, tin        2-ethylhexanoate, copper 2-ethylhexanoate, zinc        2-ethylhexanoate, tin oleate, copper oleate, zinc oleate, tin        phosphate, copper phosphate, zinc phosphate, tin benzoate,        copper benzoate and zinc benzoate;    -   (t) metal salts, such as copper hydroxycarbonate, sodium        dichromate, potassium dichromate, potassium chromate, copper        sulphate, copper chloride, copper borate, zinc fluorosilicate,        copper fluorosilicate, and mixtures with fixatives;    -   (u) oxides, such as tributyltin oxide, Cu₂O, CuO, ZnO;    -   (v) dialkyldithiocarbamates, such as Na and Zn salts of        dialkyldithiocarbamates, tetramethylthiuram disulphide,        potassium N-methyl-dithiocarbamate;    -   (w) nitriles, such as 2,4,5,6-tetrachloroisophthalodinitrile,        disodium cyano-dithioimidocarbamate;    -   (x) quinolines, such as 8-hydroxyquinoline, and their Cu salts;    -   (y) mucochloric acid, 5-hydroxy-2(5H)-furanone;    -   (z) 4,5-dichlorodithiazolinone, 4,5-benzodithiazolinone,        4,5-trimethylenedithiazolinone,        4,5-dichloro-(3H)-1,2-dithiol-3-one,        3,5-dimethyl-tetrahydro-1,3,5-thiadiazine-2-thione,        N-(2-p-chlorobenzoylethyl)-hexaminium chloride, potassium        N-hydroxymethyl-N′-methyl-dithiocarbamate,        2-oxo-2-(4-hydroxy-phenyl)acetohydroximic acid chloride,        phenyl-(2-chloro-cyano-vinyl)sulphone,        phenyl-(1,2-dichloro-2-cyano-vinyl)sulphone; and    -   (aa) Ag-, Zn- or Cu-containing zeolites, alone or enclosed in        polymeric active compounds, or    -   (bb) mixtures of more than one of the abovementioned fungicides.

Particularly favorable mixing components are, for example, the followingcompounds:

Fungicides:

-   -   Inhibitors of nucleic acid synthesis which include but are not        limited to benalaxyl, benalaxyl-M, bupirimate, chiralaxyl,        clozylacon, dimethirimol, ethirimol, furalaxyl, hymexazol,        metalaxyl, metalaxyl-M, ofurace, oxadixyl, oxolinic acid;    -   Inhibitors of mitosis and cell division which include but are        not limited to benomyl, carbendazim, diethofencarb,        fuberidazole, pencycuron, thiabendazole, thiophanat-methyl,        zoxamide;    -   Inhibitors of respiratory chain complex I which include but are        not limited to diflumetorim;    -   Inhibitors of respiratory chain complex II which include but are        not limited to boscalid, carboxin, fenfuram, flutolanil,        furametpyr, mepronil, oxycarboxin, penthiopyrad, thifluzamide;    -   Inhibitors of respiratory chain complex III which include but        are not limited to azoxystrobin, cyazofamid, dimoxystrobin,        enestrobin, famoxadone, fenamidone, fluoxastrobin,        kresoxim-methyl, metominostrobin, orysastrobin, pyraclostrobin,        picoxystrobin;    -   Decouplers which include but are not limited to dinocap,        fluazinam;    -   Inhibitors of ATP production which include but are not limited        to fentin acetate, fentin chloride, fentin hydroxide,        silthiofam;    -   Inhibitors of amino acid biosynthesis and protein biosynthesis        which include but are not limited to andoprim, blasticidin-S,        cyprodinil, kasugamycin, kasugamycin hydrochloride hydrate,        mepanipyrim, pyrimethanil;    -   Inhibitors of signal transduction which include but are not        limited to fenpiclonil, fludioxonil, quinoxyfen;    -   Inhibitors of lipid and membrane synthesis which include but are        not limited to chlozolinate, iprodione, procymidone,        vinclozolin, ampropylfos, potassium-ampropylfos, edifenphos,        iprobenfos (IBP), isoprothiolane, pyrazophos, tolclofos-methyl,        biphenyl, iodocarb, propamocarb, propamocarb hydrochloride;    -   Inhibitors of ergosterol biosynthesis which include but are not        limited to fenhexamid, azaconazole, bitertanol, bromuconazole,        cyproconazole, diclobutrazole, difenoconazole, diniconazole,        diniconazole-M, epoxiconazole, etaconazole, fenbuconazole,        fluquinconazole, flusilazole, flutriafol, furconazole,        furconazole-cis, hexaconazole, imibenconazole, ipconazole,        metconazole, myclobutanil, paclobutrazole, penconazole,        propiconazole, prothioconazole, simeconazole, tebuconazole,        tetraconazole, triadimefon, triadimenol, triticonazole,        uniconazole, voriconazole, imazalil, imazalil sulphate,        oxpoconazole, fenarimol, flurprimidole, nuarimol, pyrifenox,        triforine, pefurazoate, prochloraz, triflumizole, viniconazole,        aldimorph, dodemorph, dodemorph acetate, fenpropimorph,        tridemorph, fenpropidin, spiroxamine, naftifine, pyributicarb,        terbinafine;    -   Inhibitors of cell wall synthesis which include but are not        limited to benthiavalicarb, bialaphos, dimethomorph, flumorph,        iprovalicarb, polyoxins, polyoxorim, validamycin A;    -   Inhibitors of melanin biosynthesis which include but are not        limited to capropamid, diclocymet, fenoxanil, phthalid,        pyroquilon, tricyclazole;    -   Resistance inductors which include but are not limited to        acibenzolar-5-methyl, probenazole, tiadinil;    -   Multisite which include but are not limited to captafol, captan,        chlorothalonil, copper salts such as: copper hydroxide, copper        naphthenate, copper oxychloride, copper sulphate, copper oxide,        oxine-copper and Bordeaux mixture, dichlofluanid, dithianon,        dodine, dodine free base, ferbam, folpet, fluorofolpet,        guazatine, guazatine acetate, iminoctadine, iminoctadine        albesilate, iminoctadine triacetate, mancopper, mancozeb, maneb,        metiram, metiram zinc, propineb, sulphur and sulphur        preparations containing calcium polysulphide, thiram,        tolylfluanid, zineb, ziram;    -   Unknown mechanism which include but are not limited to        amibromdol, benthiazol, bethoxazin, capsimycin, carvone,        chinomethionat, chloropicrin, cufraneb, cyflufenamid, cymoxanil,        dazomet, debacarb, diclomezine, dichlorophen, dicloran,        difenzoquat, difenzoquat methyl sulphate, diphenylamine,        ethaboxam, ferimzone, flumetover, flusulphamide, fluopicolide,        fluoroimide, hexachlorobenzene, 8-hydroxyquinoline sulphate,        irumamycin, methasulphocarb, metrafenone, methyl isothiocyanate,        mildiomycin, natamycin, nickel dimethyl dithiocarbamate,        nitrothal-isopropyl, octhilinone, oxamocarb, oxyfenthiin,        pentachlorophenol and salts, 2-phenylphenol and salts,        piperalin, propanosine-sodium, proquinazid, pyrrol nitrin,        quintozene, tecloftalam, tecnazene, triazoxide, trichlamide,        zarilamid and 2,3,5,6-tetrachloro-4-(methylsulphonyl)pyridine,        N-(4-chloro-2-nitrophenyl)-N-ethyl-4-methylbenzenesulphonamide,        2-amino-4-methyl-N-phenyl-5-thiazolecarboxamide,        2-chloro-N-(2,3-dihydro-1,1,3-trimethyl-1H-inden-4-yl)-3-pyridinecarboxamide,        3-[5-(4-chlorophenyl)-2,3-dimethylisoxazolidin-3-yl]pyridine,        cis-1-(4-chlorophenyl)-2-(1H-1,2,4-triazol-1-yl)cycloheptanol,        2,4-dihydro-5-methoxy-2-methyl-4-[[[[1-[3-(trifluoromethyl)phenyl]ethylidene]amino]oxy]methyl]phenyl]-3H-1,2,3-triazol-3-one        (185336-79-2), methyl        1-(2,3-dihydro-2,2-dimethyl-1H-inden-1-yl)-1H-imidazole-5-carboxylate,        3,4,5-trichloro-2,6-pyridinedicarbonitrile, methyl        2-[[[cyclopropyl[(4-methoxyphenyl)imino]methyl]thio]methyl]-.alpha.-(methoxymethylene)benzacetate,        4-chloro-alpha-propynyloxy-N-[2-[3-methoxy-4-(2-propynyloxy)phenyl]ethyl]benzacetamide,        (2S)-N-[2-[4-[[3-(4-chlorophenyl)-2-propynyl]oxy]-3-methoxyphenyl]ethyl]-3-methyl-2-[(methylsulphonyl)amino]butanamide,        5-chloro-7-(4-methylpiperidin-1-yl)-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine,        5-chloro-6-(2,4,6-trifluorophenyl)-N-[(1R)-1,2,2-trimethylpropyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine,        5-chloro-N-[(1R)-1,2-dimethylpropyl]-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine,        N-[1-(5-bromo-3-chloropyridin-2-yl)ethyl]-2,4-dichloronicotinamide,        N-(5-bromo-3-chloropyridin-2-yl)methyl-2,4-dichloronicotinamide,        2-butoxy-6-iodo-3-propylbenzopyranon-4-one,        N-{(Z)-[(cyclopropylmethoxy)imino][6-(difluoromethoxy)-2,3-difluorophenyl]methyl}-2-benzacetamide,        N-(3-ethyl-3,5,5-trimethylcyclohexyl)-3-formylamino-2-hydroxybenzamide,        2-[[[[1-[3(1-fluoro-2-phenylethyl)oxy]phenyl]ethylidene]amino]oxy]methyl]-alpha-(methoxyimino)-N-methyl-alphaE-benzacetamide,        N-{2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]ethyl}-2-(trifluoromethyl)benzamide,        N-(3′,4′-dichloro-5-fluorobiphenyl-2-yl)-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide,        N-(6-methoxy-3-pyridinyl)cyclopropanecarboxamide,        1-[(4-methoxyphenoxy)methyl]-2,2-dimethylpropyl-1H-imidazole-1-carboxylic        acid,        O-[1-[(4-methoxyphenoxy)methyl]-2,2-dimethylpropyl]-1H-imidazole-1-carbothioic        acid,        2-(2-{[6-(3-chloro-2-methylphenoxy)-5-fluoropyrimidin-4-yl]oxy}phenyl)-2-(methoxyimino)-N-methyl-acetamide;

Bactericides:

which include but are not limited to bronopol, dichlorophen, nitrapyrin,nickel dimethyldithiocarbamate, kasugamycin, octhilinone,furancarboxylic acid, oxytetracycline, probenazole, streptomycin,tecloftalam, copper sulphate and other copper preparations.

Insecticides/Acaricides/Nematicides:

-   -   Acetylcholine esterase (AChE) inhibitors;    -   Carbamates which include but are not limited to alanycarb,        aldicarb, aldoxycarb, allyxycarb, aminocarb, bendiocarb,        benfuracarb, bufencarb, butacarb, butocarboxim, butoxycarboxim,        carbaryl, carbofuran, carbosulphan, cloethocarb, dimetilan,        ethiofencarb, fenobucarb, fenothiocarb, formetanate,        furathiocarb, isoprocarb, metam-sodium, methiocarb, methomyl,        metolcarb, oxamyl, pirimicarb, promecarb, propoxur, thiodicarb,        thiofanox, trimethacarb, XMC, xylylcarb, triazamate;    -   Organophosphates which include but are not limited to acephate,        azamethiphos, azinphos (-methyl, -ethyl), bromophos-ethyl,        bromfenvinfos (-methyl), butathiofos, cadusafos,        carbophenothion, chlorethoxyfos, chlorfenvinphos, chlormephos,        chlorpyrifos (-methyl/-ethyl), coumaphos, cyanofenphos,        cyanophos, chlorfenvinphos, demeton-S-methyl,        demeton-S-methylsulphone, dialifos, diazinon, dichlofenthion,        dichlorvos/DDVP, dicrotophos, dimethoate, dimethylvinphos,        dioxabenzofos, disulphoton, EPN, ethion, ethoprophos, etrimfos,        famphur, fenamiphos, fenitrothion, fensulphothion, fenthion,        flupyrazofos, fonofos, formothion, fosmethilan, fosthiazate,        heptenophos, iodofenphos, iprobenfos, isazofos, isofenphos,        isopropyl O-salicylate, isoxathion, malathion, mecarbam,        methacrifos, methamidophos, methidathion, mevinphos,        monocrotophos, naled, omethoate, oxydemeton-methyl, parathion        (-methyl/-ethyl), phenthoate, phorate, phosalone, phosmet,        phosphamidon, phosphocarb, phoxim, pirimiphos (-methyl/-ethyl),        profenofos, propaphos, propetamphos, prothiofos, prothoate,        pyraclofos, pyridaphenthion, pyridathion, quinalphos, sebufos,        sulphotep, sulprofos, tebupirimfos, temephos, terbufos,        tetrachlorvinphos, thiometon, triazophos, triclorfon,        vamidothion;    -   Sodium channel modulators/voltage-dependent sodium channel        blockers;    -   Pyrethroids which include but are not limited to acrinathrin,        allethrin (d-cis-trans, d-trans), beta-cyfluthrin, bifenthrin,        bioallethrin, bioallethrin-S-cyclopentyl isomer,        bioethanomethrin, biopermethrin, bioresmethrin, chlovaporthrin,        cis-cypermethrin, cis-resmethrin, cis-permethrin, clocythrin,        cycloprothrin, cyfluthrin, cyhalothrin, cypermethrin (alpha-,        beta-, theta-, zeta-), cyphenothrin, deltamethrin, empenthrin        (1R isomer), esfenvalerate, etofenprox, fenfluthrin,        fenpropathrin, fenpyrithrin, fenvalerate, flubrocythrinate,        flucythrinate, flufenprox, flumethrin, fluvalinate, fubfenprox,        gamma-cyhalothrin, imiprothrin, kadethrin, lambda-cyhalothrin,        metofluthrin, permethrin (cis-, trans-), phenothrin        (1R-trans-isomer), prallethrin, profluthrin, protrifenbute,        pyresmethrin, resmethrin, RU 15525, silafluofen,        tau-fluvalinate, tefluthrin, terallethrin, tetramethrin (1R        isomer), tralomethrin, transfluthrin, ZXI 8901, pyrethrins        (pyrethrum);    -   DDT;    -   Oxadiazines which include but are not limited to indoxacarb;    -   Semicarbazones which include but are not limited to        metaflumizone (BAS3201);    -   Acetylcholine receptor agonists/antagonists which include but        are not limited to chloronicotinyls, for example, acetamiprid,        clothianidin, dinotefuran, imidacloprid, nitenpyram, nithiazine,        thiacloprid, imidaclothiz, AKD-1022, thiamethoxam, nicotine,        bensultap, cartap;    -   Acetylcholine receptor modulators which include but are not        limited to spinosyns, for example, spinosad, spinetoram        (XDE-175);    -   GABA-controlled chloride channel antagonists which include but        are not limited to organochlorines, for example, camphechlor,        chlordane, endosulphan, gamma-HCH, HCH, heptachlor, lindane,        methoxychlor; fiprols, for example, acetoprole, ethiprole,        fipronil, pyrafluprole, pyriprole, vaniliprole    -   Chloride channel activators which include but are not limited to        avermectins and milbemycins, for example, abarmectin, emamectin,        emamectin-benzoate, ivermectin, lepimectin, milbemycin,        milbemycin oxime, selamectin, doramectin, dimadectin,        moxidectin;    -   Juvenile hormone mimetics which include but are not limited to        example diofenolan, epofenonane, fenoxycarb, hydroprene,        kinoprene, methoprene, pyriproxifen, triprene;    -   Ecdysone agonists/disruptors which include but are not limited        to diacylhydrazines, for example, chromafenozide, halofenozide,        methoxyfenozide, tebufenozide;    -   Chitin biosynthesis inhibitors which include but are not limited        to benzoylureas, for example, bistrifluoron, chlofluazuron,        diflubenzuron, fluazuron, flucycloxuron, flufenoxuron,        hexaflumuron, lufenuron, novaluron, noviflumuron, penfluoron,        teflubenzuron, triflumuron; buprofezin, cyromazine;    -   Oxidative phosphorylation inhibitors, ATP disruptors which        include but are not limited to diafenthiuron, organotin        compounds, for examples, azocyclotin, cyhexatin,        fenbutatin-oxide;    -   Oxidative phosphorylation decouplers acting by interrupting the        H-proton gradient which include but are not limited to pyrroles,        for example, chlorfenapyr; dinitrophenols, for example,        binapacyrl, dinobuton, dinocap, DNOC    -   Site-I electron transport inhibitors which include but are not        limited to METIs, for example, fenazaquin, fenpyroximate,        pyrimidifen, pyridaben, tebufenpyrad, tolfenpyrad;        hydramethylnon, dicofol;    -   Site-II electron transport inhibitors which include but are not        limited to rotenone;    -   Site-III electron transport inhibitors which include but are not        limited to acequinocyl, fluacrypyrim;    -   Microbial disruptors of the insect gut membrane    -   Bacillus thuringiensis strains;    -   Lipid synthesis inhibitors which include but are not limited to        tetronic acids, for example, spirodiclofen, spiromesifen;        tetramic acids, for example spirotetramat; carboxamides, for        example, flonicamid; octopaminergic agonists, for example,        amitraz;    -   Inhibitors of magnesium-stimulated ATPase which include but are        not limited to propargite, nereistoxin analogs, for example,        thiocyclam hydrogen oxalate, thiosultap-sodium;    -   Ryanodin receptor agonists which include but are not limited to        benzoic acid dicarboxamides, for example, flubendiamid;        anthronilamides, for example, pynaxypyr        (3-bromo-N-{4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl}-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide);    -   Biologicals, hormones or pheromones which include but are not        limited to azadirachtin, Bacillus spec., Beauveria spec.,        codlemone, Metarrhizium spec., Paecilomyces spec.,        thuringiensin, Verticillium spec.;    -   Active compounds with unknown or unspecific mechanisms of action        which include but are not limited to fumigants, for example        aluminium phosphide, methyl bromide, sulphuryl fluoride,        antifeedants, for example cryolite, flonicamid, pymetrozine,        mite growth inhibitors, for example clofentezine, etoxazole,        hexythiazox; amidoflumet, benclothiaz, benzoximate, bifenazate,        bromopropylate, buprofezin, chinomethionat, chlordimeform,        chlorobenzilate, chloropicrin, clothiazoben, cycloprene,        cyflumetofen, dicyclanil, fenoxacrim, fentrifanil, flubenzimine,        flufenerim, flutenzin, gossyplure, hydramethylnone, japonilure,        metoxadiazone, petroleum, piperonyl butoxide, potassium oleate,        pyridalyl, sulphluramid, tetradifon, tetrasul, triarathene,        verbutin.

Herbicides which are known from the literature and which can bementioned, which can be combined with the compounds of the formula (I),are, for example, the following active substances (Note: the compoundsare either designated by the common name according to the InternationalOrganization for Standardization (ISO) or using the chemical name, ifappropriate together with a customary code number):

acetochlor; acifluorfen(-sodium); aclonifen; AKH 7088, i.e.[[[1-[5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrophenyl]-2-methoxyethylidene]amino]oxy]aceticacid and its methyl ester; alachlor; alloxydim(-sodium); ametryn;amicarbazone, amidochlor, amidosulfuron; amitrol; AMS, i.e. ammoniumsulfamate; anilofos; asulam; atrazine; azafenidin; azimsulfuron(DPX-A8947); aziprotryn; barban; BAS 516H, i.e.5-fluoro-2-phenyl-4H-3,1-benzoxazin-4-one; beflubutamid;benazolin(-ethyl); benfluralin; benfuresate; bensulfuron(-methyl);bensulide; bentazone(-sodium); benzobicyclone; benzofenap; benzofluor;benzoylprop(-ethyl); benzthiazuron; bialaphos (bilanafos); bifenox;bispyribac(-sodium); bromacil; bromobutide; bromofenoxim; bromoxynil;bromuron; buminafos; busoxinone; butachlor; butafenacil; butamifos;butenachlor; buthidazole; butralin; butroxydim; butylate; cafenstrole(CH-900); carbetamide; carfentrazone(-ethyl); caloxydim, CDAA, i.e.2-chloro-N,N-di-2-propenylacetamide; CDEC, i.e. 2-chloroallyldiethyldithiocarbamate; chlomethoxyfen; chloramben; chlorazifop-butyl;chlorbromuron; chlorbufam; chlorfenac; chlorflurenol-methyl;chloridazon; chlorimuron(-ethyl); chlornitrofen; chlorotoluron;chloroxuron; chlorpropham; chlorsulfuron; chlorthal-dimethyl;chlorthiamid; chlortoluron, cinidon(-methyl or -ethyl), cinmethylin;cinosulfuron; clethodim; clefoxydim, clodinafop and its esterderivatives (for example clodinafop-propargyl); clomazone; clomeprop;cloproxydim; clopyralid; clopyrasulfuron(-methyl); cloransulam(-methyl);cumyluron (JC 940); cyanazine; cycloate; cyclosulfamuron (AC 104);cycloxydim; cycluron; cyhalofop and its ester derivatives (for examplebutyl-ester, DEH-112); cyperquat; cyprazine; cyprazole; daimuron; 2,4-D;2,4-DB; dalapon; dazomet, desmedipham; desmetryn; di-allate; dicamba;dichlobenil; dichlorprop(-P); diclofop and its esters such asdiclofop-methyl; diclosulam, diethatyl(-ethyl); difenoxuron;difenzoquat; diflufenican; diflufenzopyr; dimefuron; dimepiperate;dimethachlor; dimethametryn; dimethenamid (SAN-582H); dimethenamid(-P);dimethazone, dimethipin; dimexyflam, dimetrasulfuron, dinitramine;dinoseb; dinoterb; diphenamid; dipropetryn; diquat; dithiopyr; diuron;DNOC; eglinazine-ethyl; EL 77, i.e.5-cyano-1-(1,1-dimethylethyl)-N-methyl-1H-pyrazole-4-carboxamide;endothal; epoprodan, EPTC; esprocarb; ethalfluralin;ethametsulfuron-methyl; ethidimuron; ethiozin; ethofumesate; ethoxyfenand its esters (for example ethyl ester, HC-252), ethoxysulfuron,etobenzanid (HW 52); F5231, i.e.N-[2-chloro-4-fluoro-5-[4-(3-fluoropropyl)-4,5-dihydro-5-oxo-1H-tetrazol-1-yl]-phenyl]ethanesulfonamide;fenoprop; fenoxan, fenoxaprop and fenoxaprop-P and their esters, forexample fenoxaprop-P-ethyl and fenoxaprop-ethyl; fenoxydim;fentrazamide; fenuron; flamprop(-methyl or -isopropyl or -isopropyl-L);flazasulfuron; florasulam; fluazifop and fluazifop-P and their esters,for example fluazifop-butyl and fluazifop-P-butyl; fluazolate,flucarbazone(-sodium); fluchloralin; flufenacet (FOE 5043), flufenpyr,flumetsulam; flumeturon; flumiclorac(-pentyl); flumioxazin (S-482);flumipropyn; fluometuron; fluorochloridone, fluorodifen;fluoroglycofen(-ethyl); flupoxam (KNW-739); flupropacil (UBIC-4243);fluproanate, flupyrsulfuron(-methyl, or -sodium); flurenol(-butyl);fluridone; fluorochloridone; fluoroxypyr(-meptyl); flurprimidol,flurtamone; fluthiacet(-methyl); fluthiamide (also known as flufenacet);fomesafen; foramsulfuron; fosamine; furilazole (MON 13900), furyloxyfen;glufosinate(-ammonium); glyphosate(-isopropylammonium); halosafen;halosulfuron(-methyl) and its esters (for example the methyl ester,NC-319); haloxyfop and its esters; haloxyfop-P(=R-haloxyfop) and itsesters; HC-252 (diphenylether), hexazinone; imazamethabenz(-methyl);imazamethapyr; imazamox; imazapic, imazapyr; imazaquin and salts such asthe ammonium salts; imazethamethapyr; imazethapyr, imazosulfuron;indanofan; iodosulfuron-(methyl)-(sodium), ioxynil; isocarbamid;isopropalin; isoproturon; isouron; isoxaben; isoxachlortole;isoxaflutole; isoxapyrifop; karbutilate; lactofen; lenacil; linuron;MCPA; MCPB; mecoprop; mefenacet; mefluidid; mesosulfuron(-methyl);mesotrione; metam, metamifop, metamitron; metazachlor;methabenzthiazuron; methazole; methoxyphenone; methyl-dymron;metobenzuron, metobromuron; (S-)metolachlor; metosulam (XRD 511);metoxuron; metribuzin; metsulfuron-methyl; MK-616; molinate; monalide;monocarbamide dihydrogensulfate; monolinuron; monuron; MT 128, i.e.6-chloro-N-(3-chloro-2-propenyl)-5-methyl-N-phenyl-3-pyridazinamine; MT5950, i.e. N-[3-chloro-4-(1-methylethyl)-phenyl]-2-methylpentanamide;naproanilide; napropamide; naptalam; NC 310, i.e.4-(2,4-dichlorobenzoyl)-1-methyl-5-benzyloxypyrazole; neburon;nicosulfuron; nipyraclophen; nitralin; nitrofen; nitrofluorfen;norflurazon; orbencarb; oryzalin; oxadiargyl (RP-020630); oxadiazone;oxasulfuron; oxaziclomefone; oxyfluorfen; paraquat; pebulate; pelargonicacid; pendimethalin; penoxulam; pentanochlor, pentoxazone; perfluidone;pethoxamid, phenisopham; phenmedipham; picloram; picolinafen;piperophos; piributicarb; pirifenop-butyl; pretilachlor;primisulfuron(-methyl); procarbazone(-sodium); procyazine; prodiamine;profluazole, profluralin; proglinazine(-ethyl); prometon; prometryn;propachlor; propanil; propaquizafop; propazine; propham; propisochlor;propoxycarbazone(-sodium), propyzamide; prosulfalin; prosulfocarb;prosulfuron (CGA-152005); prynachlor; pyraclonil, pyraflufen(-ethyl);pyrazolinate; pyrazon; pyrazosulfuron(-ethyl); pyrazoxyfen;pyribenzoxim; pyributicarb; pyridafol; pyridate; pyriftalid,pyrimidobac(-methyl); pyrithiobac(-sodium) (KIH-2031); pyroxofop and itsesters (for example propargyl ester); quinclorac; quinmerac;quinoclamine, quinofop and its ester derivatives, quizalofop andquizalofop-P and their ester derivatives, for example quizalofop-ethyl;quizalofop-P-tefuryl and -ethyl; renriduron; rimsulfuron (DPX-E 9636); S275, i.e.2-[4-chloro-2-fluoro-5-(2-propynyloxy)phenyl]-4,5,6,7-tetrahydro-2H-indazole;secbumeton; sethoxydim; siduron; simazine; simetryn; SN 106279, i.e.2-[[7-[2-chloro-4-(trifluoromethyl)phenoxy]-2-naphthalenyl]oxy]propanoicacid and its methyl ester; sulcotrione; sulfentrazone (FMC-97285,F-6285); sulfazuron; sulfometuron(-methyl); sulfosate (ICI-A0224);sulfosulfuron; TCA; tebutam (GCP-5544); tebuthiuron; tepraloxydim;terbacil; terbucarb; terbuchlor; terbumeton; terbuthylazine; terbutryn;TFH 450, i.e.N,N-diethyl-3-[(2-ethyl-6-methylphenyl)sulfonyl]-1H-1,2,4-triazole-1-carboxamide;thenylchlor (NSK-850); thiafluamide; thiazafluoron; thiazopyr(Mon-13200); thidiazimin (SN-24085); thifensulfuron(-methyl);thiobencarb; tiocarbazil; tralkoxydim; tri-allate; triasulfuron;triaziflam; triazofenamide; tribenuron(-methyl); 2,3,6-trichlorobenzoicacid (2,3,6-TBA), triclopyr; tridiphane; trietazine;trifloxysulfuron(-sodium), trifluralin; triflusulfuron and esters (e.g.methyl ester, DPX-66037); trimeturon; tritosulfuron; tsitodef;vernolate; WL 110547, i.e.5-phenoxy-1-[3-(trifluoromethyl)phenyl]-1H-tetrazole; UBH-509; D-489; LS82-556; KPP-300; NC-324; NC-330; KH-218; DPX-N8189; SC-0774; DOWCO-535;DK-8910; V-53482; PP-600; MBH-001; KIH-9201; ET-751; KIH-6127; KIH-2023and KIH5996.

Appropriate herbicide safeners include but are not limited to benoxacor,cloquintocet, cyometrinil, cyprosulfamide, dichlormid, dicyclonon,dietholate, fenchlorazole, fenclorim, flurazole, fluxofenim, furilazole,isoxadifen, mefenpyr, mephenate, naphthalic anyhydride and oxabetrinil.

Components which may be employed for the active substances according tothe invention in mixed formulations, for example, known active compoundswhich are based on an inhibition of, for example, acetolactate synthase,acetyl-coenzyme A carboxylase, PS I, PS II, HPPDO, phytoene desaturase,protoporphyrinogen oxidase, glutamine synthetase, cellulosebiosynthesis, 5-enolpyruvylshikimate-3-phosphate synthetase. Suchcompounds, and also other compounds which can be employed, whosemechanism of action is to a degree unknown or different, are described,for example, in Weed Research 26, 441-445 (1986), or “The PesticideManual”, 12th Edition 2000 (hereinbelow also abbreviated to “PM”), TheBritish Crop Protection Council and the Royal Soc. of Chemistry(editors) and literature cited therein.

The compounds of formula (I) can be formulated in various ways,depending on the prevailing biological and/or chemico-physicalparameters. Examples of possible formulations which are suitable are:wettable powders (WP), water-soluble powders (SP), water-solubleconcentrates, emulsifiable concentrates (EC), emulsions (EW) such asoil-in-water and water-in-oil emulsions, sprayable solutions, suspensionconcentrates (SC), dispersions on an oil or water basis, solutions whichare miscible with oil, capsule suspensions (CS), dusts (DP),seed-dressing products, granules for broadcasting and soil application,granules (GR) in the form of microgranules, spray granules, coatedgranules and adsorption granules, water-dispersible granules (WG),water-soluble granules (SG), ULV formulations, microcapsules and waxes.

The formulations mentioned can be prepared in a manner known per se, forexample by mixing the active compounds with at least one solvent ordiluent, emulsifier, dispersant and/or binder or fixative, waterrepellent and optionally one or more of a desiccant, UV stabilizer, acolorant, a pigment and other processing auxiliaries.

These individual formulation types are known in principle and described,for example, in: Winnacker-Küchler, “Chemische Technologie” [ChemicalTechnology], Volume 7, C. Hauser Verlag, Munich, 4th Edition 1986; Wadevan Valkenburg, “Pesticide Formulations”, Marcel Dekker, N.Y., 1973; K.Martens, “Spray Drying Handbook”, 3rd Ed. 1979, G. Goodwin Ltd. London.The necessary formulation auxiliaries such as inert materials,surfactants, solvents and other additives are also known and described,for example, in: Watkins, “Handbook of Insecticide Dust Diluents andCarriers”, 2nd Ed., Darland Books, Caldwell N.J.; H.v. Olphen,“Introduction to Clay Colloid Chemistry”, 2nd Ed., J. Wiley & Sons,N.Y.; C. Marsden, “Solvents Guide”, 2nd Ed., Interscience, N.Y. 1963;McCutcheon's “Detergents and Emulsifiers Annual”, MC Publ. Corp.,Ridgewood N.J.; Sisley and Wood, “Encyclopedia of Surface ActiveAgents”, Chem. Publ. Co. Inc., N.Y. 1964; Schönfeldt,“Grenzflächenaktive Äthylenoxidaddukte” [Surface-active ethylene oxideadducts], Wiss. Verlagsgesell, Stuttgart 1976; Winnacker-Küchler,“Chemische Technologie” [Chemical Technology], Volume 7, C. HauserVerlag, Munich, 4th Ed. 1986.

Wettable powders are preparations which are uniformly dispersible inwater and which, besides the compounds of formula (I), also compriseionic and/or nonionic surfactants (wetters, dispersants), for example,polyoxyethylated alkylphenols, polyoxyethylated fatty alcohols,polyoxyethylated fatty amines, fatty alcohol polyglycol ether sulfates,alkanesulfonates or alkylbenzenesulfonates, sodium lignosulfonate,sodium 2,2′-dinaphthylmethane-6,6′-disulfonate, sodiumdibutylnaphthalenesulfonate or else sodium oleoylmethyltaurinate, inaddition to a diluent or inert substance. To prepare the wettablepowders, the compounds of formula (I) are, for example, ground finely inconventional apparatuses such as hammer mills, blower mills and air-jetmills and mixed with the formulation auxiliaries, either concomitantlyor thereafter.

Emulsifiable concentrates are prepared, for example, by dissolving thecompounds of formula (I) in an organic solvent, for example butanol,cyclohexanone, dimethylformamide, xylene or else higher-boilingaromatics or hydrocarbons or mixtures of these, with addition of one ormore ionic and/or nonionic surfactants (emulsifiers). Emulsifiers whichcan be used are, for example: calcium salts of alkylarylsulfonic acids,such as calcium dodecylbenzenesulfonate or nonionic emulsifiers, such asfatty acid polyglycol esters, alkylaryl polyglycol ethers, fatty alcoholpolyglycol ethers, propylene oxide/ethylene oxide condensates, alkylpolyethers, sorbitan esters such as sorbitan fatty acid esters orpolyoxyethylene sorbitan esters such as polyoxyethylene sorbitan fattyacid esters.

Dusts are obtained by grinding the active substance with finely dividedsolid substances, for example talc or natural clays, such as kaolin,bentonite or pyrophyllite, or diatomaceous earth.

Suspension concentrates may be water- or oil-based. They can beprepared, for example, by wet grinding by means of commerciallyavailable bead mills, if appropriate with addition of surfactants, asthey have already been mentioned above for example in the case of theother formulation types.

Emulsions, for example oil-in-water emulsions (EW), can be prepared forexample by means of stirrers, colloid mills and/or static mixtures usingaqueous organic solvents and, if appropriate, surfactants as they havealready been mentioned above for example in the case of the otherformulation types.

Granules can be prepared either by spraying the compounds of formula (I)onto adsorptive, granulated inert material or by applying activesubstance concentrates onto the surface of carriers such as sand,kaolinites or of granulated inert material, by means of binders, forexample polyvinyl alcohol, sodium polyacrylate or alternatively mineraloils. Suitable active substances can also be granulated in the mannerwhich is conventional for the production of fertilizer granules, ifdesired in a mixture with fertilizers.

Water-dispersible granules are prepared, as a rule, by the customaryprocesses such as spray-drying, fluidized-bed granulation, diskgranulation, mixing in high-speed mixers and extrusion without solidinert material. To prepare disk, fluidized-bed, extruder and spraygranules, see, for example, processes in “Spray-Drying Handbook” 3rd ed.1979, G. Goodwin Ltd., London; J. E. Browning, “Agglomeration”, Chemicaland Engineering 1967, pages 147 et seq.; “Perry's Chemical Engineer'sHandbook”, 5th Ed., McGraw-Hill, New York 1973, p. 8-57.

In general, the agrochemical preparations comprise a range selected fromthe group consisting of about 0.1 to about 99% by weight and about 0.1to about 95% by weight, of compounds of formula (I).

The concentration of compounds of formula (I) in wettable powders is,for example, about 10 to about 90% by weight, the remainder to 100% byweight being composed of customary formulation components. In the caseof emulsifiable concentrates, the concentration of compounds of formula(I) can amount to ranges selected from the group consisting of about 1%to about 90% and about 5% to about 80% by weight. Formulations in theform of dusts usually comprise in the range selected from the groupconsisting of about 1% to about 30% by weight of compounds of formula(I) and about 5% to about 20% by weight of compounds of formula (I). Forsprayable solutions comprise a range selected from the group consistingof about 0.05% to about 80% by weight of compounds of formula (I) andabout 2% to about 50% by weight of compounds of formula (I). In the caseof water-dispersible granules, the content of compounds of formula (I)depends partly on whether the compounds of formula (I) are in liquid orsolid form and on which granulation auxiliaries, fillers and the likeare being used. The water-dispersible granules, for example, comprise arange selected from the group consisting of between about 1 and about95% and between about 10% and about 80% by weight.

In addition, the formulations of compounds of formula (I) mentionedcomprise, if appropriate, the adhesives, wetters, dispersants,emulsifiers, penetrants, preservatives, antifreeze agents, solvents,fillers, carriers, colorants, antifoams, evaporation inhibitors, pHregulators and viscosity regulators which are conventional in each case.

The mixtures according to the invention can be applied via the soileither pre-emergently or post-emergently. The mixtures according to theinvention can also be applied via the leaf. The mixtures according tothe invention can be employed for seed dressing. It is also possible toapply the mixtures according to the invention via an irrigation system,for example via the water for irrigation.

When used as insecticides, the active compounds according to theinvention can furthermore be present in their commercially availableformulations and in the use forms, prepared from these formulations, asa mixture with synergists. Synergists are compounds which increase theaction of the active compounds, without it being necessary for thesynergistic agent added to be active itself.

When used as insecticides, the active compounds according to theinvention can furthermore be present in their commercially availableformulations and in the use forms, prepared from these formulations, asa mixture with inhibitors which reduce degradation of the activecompound after use in the environment of the plant, on the surface ofparts of plants or in plant tissues.

The active compound content of the use forms prepared from thecommercially available formulations can vary within wide limits. Theactive compound concentration of the use forms can be from about0.00000001 to about 95% by weight of active compound, preferably betweenabout 0.00001 and about 1% by weight.

The active compounds are employed in a customary manner appropriate forthe use forms.

All plants and plant parts can be treated in accordance with theinvention. Plants are to be understood as meaning in the present contextall plants and plant populations such as desired and undesired wildplants or crop plants (including naturally occurring crop plants). Cropplants can be plants which can be obtained by conventional plantbreeding and optimization methods or by biotechnological and geneticengineering methods or by combinations of these methods, including thetransgenic plants and including the plant cultivars protectable or notprotectable by plant breeders' rights. Plant parts are to be understoodas meaning all parts and organs of plants above and below the ground,such as shoot, leaf, flower and root, examples which may be mentionedbeing leaves, needles, stalks, stems, flowers, fruit bodies, fruits,seeds, roots, tubers and rhizomes. The plant parts also includeharvested material, and vegetative and generative propagation material,for example cuttings, tubers, rhizomes, offshoots and seeds.

Treatment according to the invention of the plants and plant parts withthe active compounds is carried out directly or by allowing thecompounds to act on the surroundings, habitat or storage space by thecustomary treatment methods, for example by immersion, spraying,evaporation, fogging, scattering, painting on, injection and, in thecase of propagation material, in particular in the case of seeds, alsoby applying one or more coats.

The active compounds according to the invention are particularlysuitable for treating seed. Here, the active compounds according to theinvention mentioned above as preferred or particularly preferred may bementioned as being preferred. Thus, a large part of the damage to cropplants which is caused by pests occurs as early as when the seed isattacked during storage and after the seed is introduced into the soil,during and immediately after germination of the plants. This phase isparticularly critical since the roots and shoots of the growing plantare particularly sensitive and even minor damage can lead to the deathof the whole plant. Protecting the seed and the germinating plant by theuse of suitable active compounds is therefore of particularly greatinterest.

The control of pests by treating the seeds of plants has been known fora long time and is the subject of continuous improvements. However, thetreatment of seed entails a series of problems which cannot always besolved in a satisfactory manner. Thus, it is desirable to developmethods for protecting the seed and the germinating plant which dispensewith the additional application of crop protection agents after sowingor after the emergence of the plants. It is furthermore desirable tooptimize the amount of active compound employed in such a way as toprovide maximum protection for the seed and the germinating plant fromattack by pests, but without damaging the plant itself by the activecompound employed. In particular, methods for the treatment of seedshould also take into consideration the intrinsic insecticidalproperties of transgenic plants in order to achieve optimum protectionof the seed and the germinating plant with a minimum of crop protectionagents being employed.

The present invention therefore in particular also relates to a methodfor the protection of seed and germinating plants from attack by pests,by treating the seed with an active compound according to the invention.The invention likewise relates to the use of the active compoundsaccording to the invention for the treatment of seed for protecting theseed and the resultant plant from pests. Furthermore, the inventionrelates to seed which has been treated with an active compound accordingto the invention so as to afford protection from pests.

One of the advantages of the present invention is that the particularsystemic properties of the active compounds according to the inventionmean that treatment of the seed with these active compounds not onlyprotects the seed itself, but also the resulting plants after emergence,from pests. In this manner, the immediate treatment of the crop at thetime of sowing or shortly thereafter can be dispensed with.

Furthermore, it must be considered as advantageous that the activecompounds according to the invention can also be employed in particularin transgenic seed, the plants arising from this seed being capable ofexpressing a protein directed against pests. By treating such seed withthe active compounds according to the invention, certain pests can becontrolled merely by the expression of the, for example, insecticidalprotein, and additionally be protected by the active compounds accordingto the invention against damage.

The active compounds according to the invention are suitable forprotecting seed of any plant variety as already mentioned above which isemployed in agriculture, in the greenhouse, in forests or inhorticulture. In particular, this takes the form of seed of maize,peanut, canola, oilseed rape, poppy, soya beans, cotton, beet (forexample sugar beet and fodder beet), rice, sorghum and millet, wheat,barley, oats, rye, sunflower, tobacco, potatoes or vegetables (forexample tomatoes, cabbage plants). The active compounds according to theinvention are likewise suitable for treating the seed of fruit plantsand vegetables as already mentioned above. The treatment of the seed ofmaize, soya beans, cotton, wheat and canola or oilseed rape is ofparticular importance.

As already mentioned above, the treatment of transgenic seed with anactive compound according to the invention is also of particularimportance. This takes the form of seed of plants which, as a rule,comprise at least one heterologous gene which governs the expression ofa polypeptide with in particular insecticidal properties. In thiscontext, the heterologous genes in transgenic seed may be derived frommicroorganisms such as Bacillus, Rhizobium, Pseudomonas, Serratia,Trichoderma, Clavibacter, Glomus or Gliocladium. The present inventionis particularly suitable for the treatment of transgenic seed whichcomprises at least one heterologous gene orignating from Bacillus sp.and whose gene product shows activity against the European corn borerand/or the corn root worm. It is particularly preferably a heterologousgene derived from Bacillus thuringiensis.

In the context of the present invention, the active compound accordingto the invention is applied to the seed either alone or in a suitableformulation. Preferably, the seed is treated in a state which is stableenough to avoid damage during treatment. In general, the seed may betreated at any point in time between harvest and sowing. The seedusually used has been separated from the plant and freed from cobs,shells, stalks, coats, hairs or the flesh of the fruits.

When treating the seed, care must generally be taken that the amount ofthe active compound according to the invention applied to the seedand/or the amount of further additives is chosen in such a way that thegermination of the seed is not adversely affected, or that the resultingplant is not damaged. This must be borne in mind in particular in thecase of active compounds which may have phytotoxic effects at certainapplication rates.

As already mentioned above, it is possible to treat all plants and theirparts according to the invention. In a preferred embodiment, wild plantspecies and plant cultivars, or those obtained by conventionalbiological breeding methods, such as crossing or protoplast fusion, andparts thereof, are treated. In a further preferred embodiment,transgenic plants and plant cultivars obtained by genetic engineeringmethods, if appropriate in combination with conventional methods(Genetically Modified Organisms), and parts thereof are treated. Theterms “parts”, “parts of plants” and “plant parts” have been explainedabove.

Particularly preferably, plants of the plant cultivars which are in eachcase commercially available or in use are treated according to theinvention. Plant cultivars are to be understood as meaning plants havingnovel properties (“traits”) which have been obtained by conventionalbreeding, by mutagenesis or by recombinant DNA techniques. These can becultivars, bio- or genotypes.

Depending on the plant species or plant cultivars, their location andgrowth conditions (soils, climate, vegetation period, diet), thetreatment according to the invention may also result in superadditive(“synergistic”) effects. Thus, for example, reduced application ratesand/or a widening of the activity spectrum and/or an increase in theactivity of the active compounds and compositions which can be usedaccording to the invention, better plant growth, increased tolerance tohigh or low temperatures, increased tolerance to drought or to water orsoil salt content, increased flowering performance, easier harvesting,accelerated maturation, higher harvest yields, higher quality and/or ahigher nutritional value of the harvested products, better storagestability and/or processability of the harvested products are possible,which exceed the effects which were actually to be expected.

The transgenic plants or plant cultivars (obtained by geneticengineering) which are preferably to be treated according to theinvention include all plants which, by virtue of the geneticmodification, received genetic material which imparted particularlyadvantageous, useful traits to these plants. Examples of such traits arebetter plant growth, increased tolerance to high or low temperatures,increased tolerance to drought or to water or soil salt content,increased flowering performance, easier harvesting, acceleratedmaturation, higher harvest yields, higher quality and/or a highernutritional value of the harvested products, better storage stabilityand/or processability of the harvested products. Further andparticularly emphasized examples of such traits are a better defence ofthe plants against animal and microbial pests, such as against insects,mites, phytopathogenic fungi, bacteria and/or viruses, and alsoincreased tolerance of the plants to certain herbicidally activecompounds. Examples of transgenic plants which may be mentioned are theimportant crop plants, such as cereals (wheat, rice), maize, soya beans,potatoes, sugar beet, tomatoes, peas and other vegetable varieties,cotton, tobacco, oilseed rape and also fruit plants (with the fruitsapples, pears, citrus fruits and grapes), and particular emphasis isgiven to maize, soya beans, potatoes, cotton, tobacco and oilseed rape.Traits that are emphasized are in particular increased defence of theplants against insects, arachnids, nematodes and slugs and snails byvirtue of toxins formed in the plants, in particular those formed in theplants by the genetic material from Bacillus thuringiensis (for exampleby the genes CryIA(a), CryIA(b), CryIA(c), CryIIA, CryIIIA, CryIIIB2,Cry9c, Cry2Ab, Cry3Bb and CryIF and also combinations thereof) (referredto hereinbelow as “Bt plants”). Traits that are also particularlyemphasized are the increased defence of the plants against fungi,bacteria and viruses by systemic acquired resistance (SAR), systemin,phytoalexins, elicitors and resistance genes and correspondinglyexpressed proteins and toxins. Traits that are furthermore particularlyemphasized are the increased tolerance of the plants to certainherbicidally active compounds, for example imidazolinones,sulphonylureas, glyphosate or phosphinotricin (for example the “PAT”gene). The genes which impart the desired traits in question can also bepresent in combination with one another in the transgenic plants.Examples of “Bt plants” which may be mentioned are maize varieties,cotton varieties, soya bean varieties and potato varieties which aresold under the trade names YIELD GARD® (for example maize, cotton, soyabeans), KnockOut® (for example maize), StarLink® (for example maize),Bollgard® (Cotton), Nucotn® (Cotton) and NewLeaf® (potato). Examples ofherbicide-tolerant plants which may be mentioned are maize varieties,cotton varieties and soya bean varieties which are sold under the tradenames Roundup Ready® (tolerance to glyphosate, for example maize,cotton, soya bean), Liberty Link® (tolerance to phosphinotricin, forexample oilseed rape), IMI® (tolerance to imidazolinones) and STS®(tolerance to sulphonylureas, for example maize). Herbicide-resistantplants (plants bred in a conventional manner for herbicide tolerance)which may be mentioned include the varieties sold under the nameClearfield®) (for example maize). Of course, these statements also applyto plant cultivars having these genetic traits or genetic traits stillto be developed, which plant cultivars will be developed and/or marketedin the future.

The plants listed can be treated according to the invention in aparticularly advantageous manner with the active compounds of thegeneral formula I according to the invention. The preferred rangesstated above for the active compounds also apply to the treatment ofthese plants. Particular emphasis is given to the treatment of plantswith the active compounds specifically mentioned in the present text.

In the field of household insecticides, the active compounds accordingto the invention are used alone or in combination with other suitableactive compounds, such as phosphoric esters, carbamates, pyrethroids,neonicotinoids, growth regulators or active compounds from other knownclasses of insecticides.

It has furthermore been found that the active compounds according to theinvention also have a strong insecticidal action against insects whichdestroy industrial materials.

The following insects may be mentioned as examples and as preferred—butwithout any limitation:

Beetles, such as Hylotrupes bajulus, Chlorophorus pilosis, Anobiumpunctatum, Xestobium rufovillosum, Ptilinus pecticornis, Dendrobiumpertinex, Ernobius mollis, Priobium carpini, Lyctus brunneus, Lyctusafricanus, Lyctus planicollis, Lyctus linearis, Lyctus pubescens,Trogoxylon aequale, Minthes rugicollis, Xyleborus spec. Tryptodendronspec. Apate monachus, Bostrychus capucins, Heterobostrychus brunneus,Sinoxylon spec. Dinoderus minutus;

Hymenopterons, such as Sirex juvencus, Urocerus gigas, Urocerus gigastaignus, Urocerus augur;

Termites, such as Kalotermes flavicollis, Cryptotermes brevis,Heterotermes indicola, Reticulitermes flavipes, Reticulitermessantonensis, Reticulitermes lucifugus, Mastotermes darwinien-sis,Zootermopsis nevadensis, Coptotermes formosanus;

Bristletails, such as Lepisma saccharina.

Industrial materials in the present connection are to be understood asmeaning non-living materials, such as, preferably, plastics, adhesives,sizes, papers and cardboards, leather, wood and processed wood productsand coating compositions.

The ready-to-use compositions may, if appropriate, comprise furtherinsecticides and, if appropriate, one or more fungicides.

The active compounds according to the invention are used in aerosols,pressure-free spray products, for example pump and atomizer sprays,automatic fogging systems, foggers, foams, gels, evaporator productswith evaporator tablets made of cellulose or polymer, liquidevaporators, gel and membrane evaporators, propeller-driven evaporators,energy-free, or passive, evaporation systems, moth papers, moth bags andmoth gels, as granules or dusts, in baits for spreading or in baitstations.

Other Active Agents for Pharmaceutical/Veterinary Use

Additional pesticidally or veterinarily active ingredients, whichinclude, but are not limited to, acaricides, anthelmintics,anti-parasitics and insecticides, may also be added to the compositionsof the invention. Anti-parasitic agents can include bothectoparasiticisal and endoparasiticidal agents. These agents arewell-known in the art (see e.g. Plumb' Veterinary Drug Handbook, 5thEdition, ed. Donald C. Plumb, Blackwell Publishing, (2005) or The MerckVeterinary Manual, 9^(th) Edition, (January 2005)) and include but arenot limited to acarbose, acepromazine maleate, acetaminophen,acetazolamide, acetazolamide sodium, acetic acid, acetohydroxamic acid,acetylcysteine, acitretin, acyclovir, albendazole, albuterol sulfate,alfentanil HCl, allopurinol, alprazolam, altrenogest, amantadine HCl,amikacin sulfate, aminocaproic acid, aminopentamide hydrogen sulfate,aminophylline/theophylline, amiodarone HCl, amitraz, amitriptyline HCl,amlodipine besylate, ammonium chloride, ammonium molybdenate,amoxicillin, amoxicillin, clavulanate potassium, amphotericin Bdesoxycholate, amphotericin B lipid-based, ampicillin, amprolium HCl,antacids (oral), antivenin, apomorphione HCl, apramycin sulfate,ascorbic acid, asparaginase, aspiring, atenolol, atipamezole HCl,atracurium besylate, atropine sulfate, aurnofin, aurothioglucose,azaperone, azathioprine, azithromycin, baclofen, barbituates, benazeprilHCl, betamethasone, bethanechol chloride, bisacodyl, bismuthsubsalicylate, bleomycin sulfate, boldenone undecylenate, bromides,bromocriptine mesylate, budenoside, buprenorphine HCl, buspirone HCl,busulfan, butorphanol tartrate, cabergoline, calcitonin salmon,calcitrol, calcium salts, captopril, carbenicillin indanyl sodium,carbimazole, carboplatin, carnitine, carprofen, carvedilol, cefadroxil,cefazolin sodium, cefixime, cefoperazone sodium, cefotaxime sodium,cefotetan disodium, cefoxitin sodium, cefpodoxime proxetil, ceftazidime,ceftiofur sodium, ceftiofur HCl, ceftiaxone sodium, cephalexin,cephalosporins, cephapirin, charcoal (activated), chlorambucil,chloramphenicol, chlordiazepoxide, chlordiazepoxide +/−clidiniumbromide, chlorothiazide, chlorpheniramine maleate, chlorpromazine HCl,chlorpropamide, chlortetracycline, chorionic gonadotropin (HCG),chromium, cimetidine, ciprofloxacin, cisapride, cisplatin, citratesalts, clarithromycin, clemastine fumarate, clenbuterol HCl,clindamycin, clofazimine, clomipramine HCl, claonazepam, clonidine,cloprostenol sodium, clorazepate dipotassium, clorsulon, cloxacillin,codeine phosphate, colchicine, corticotropin (ACTH), cosyntropin,cyclophosphamide, cyclosporine, cyproheptadine HCl, cytarabine,dacarbazine, dactinomycin/actinomycin D, dalteparin sodium, danazol,dantrolene sodium, dapsone, decoquinate, deferoxamine mesylate,deracoxib, deslorelin acetate, desmopressin acetate,desoxycorticosterone pivalate, detomidine HCl, dexamethasone,dexpanthenol, dexraazoxane, dextran, diazepam, diazoxide (oral),dichlorphenamide, dichlorvos, diclofenac sodium, dicloxacillin,diethylcarbamazine citrate, diethylstilbestrol (DES), difloxacin HCl,digoxin, dihydrotachysterol (DHT), diltiazem HCl, dimenhydrinate,dimercaprol/BAL, dimethyl sulfoxide, dinoprost tromethamine,diphenylhydramine HCl, disopyramide phosphate, dobutamine HCl,docusate/DSS, dolasetron mesylate, domperidone, dopamine HCl,doramectin, doxapram HCl, doxepin HCl, doxorubicin HCl, doxycycline,edetate calcium disodium.calcium EDTA, edrophonium chloride,enalapril/enalaprilat, enoxaparin sodium, enrofloxacin, ephedrinesulfate, epinephrine, epoetin/erythropoietin, eprinomectin, epsiprantel,erythromycin, esmolol HCl, estradiol cypionate, ethacrynicacid/ethacrynate sodium, ethanol (alcohol), etidronate sodium, etodolac,etomidate, euthanasia agents w/pentobarbital, famotidine, fatty acids(essential/omega), felbamate, fenbendazole, fentanyl, ferrous sulfate,filgrastim, finasteride, fipronil, florfenicol, fluconazole,flucytosine, fludrocortisone acetate, flumazenil, flumethasone, flunixinmeglumine, fluorouracil (5-FU), fluoxetine, fluticasone propionate,fluvoxamine maleate, fomepizole (4-MP), furazolidone, furosemide,gabapentin, gemcitabine HCL, gentamicin sulfate, glimepiride, glipizide,glucagon, glucocorticoid agents, glucosamine/chondroitin sulfate,glutamine, glyburide, glycerine (oral), glycopyrrolate, gonadorelin,grisseofulvin, guaifenesin, halothane, hemoglobin glutamer-200(Oxyglobin®), heparin, hetastarch, hyaluronate sodium, hydrazaline HCl,hydrochlorothiazide, hydrocodone bitartrate, hydrocortisone,hydromorphone, hydroxyurea, hydroxyzine, ifosfamide, imidacloprid,imidocarb dipropinate, impenem-cilastatin sodium, imipramine, inaminonelactate, insulin, interferon alfa-2a (human recombinant), iodide(sodium/potassium), ipecac (syrup), ipodate sodium, iron dextran,isoflurane, isoproterenol HCl, isotretinoin, isoxsuprine HCl,itraconazole, ivermectin, kaolin/pectin, ketamine HCl, ketoconazole,ketoprofen, ketorolac tromethamine, lactulose, leuprolide, levamisole,levetiracetam, levothyroxine sodium, lidocaine HCl, lincomycin HCl,liothyronine sodium, lisinopril, lomustine (CCNU), lufenuron, lysine,magnesium, mannitol, marbofloxacin, mechlorethamine HCl, meclizine HCl,meclofenamic acid, medetomidine HCl, medium chain triglycerides,medroxyprogesterone acetate, megestrol acetate, melarsomine, melatonin,meloxican, melphalan, meperidine HCl, mercaptopurine, meropenem,metformin HCl, methadone HCl, methazolamide, methenaminemandelate/hippurate, methimazole, methionine, methocarbamol,methohexital sodium, methotrexate, methoxyflurane, methylene blue,methylphenidate, methylprednisolone, metoclopramide HCl, metoprolol,metronidaxole, mexiletine HCl, mibolerlone, midazolam HCl milbemycinoxime, mineral oil, minocycline HCl, misoprostol, mitotane, mitoxantroneHCl, morantel tartrate, morphine sulfate, moxidectin, naloxone HCl,mandrolone decanoate, naproxen, narcotic (opiate) agonist analgesics,neomycin sulfate, neostigmine, niacinamide, nitazoxanide, nitenpyram,nitrofurantoin, nitroglycerin, nitroprusside sodium, nizatidine,novobiocin sodium, nystatin, octreotide acetate, olsalazine sodium,omeprozole, ondansetron, opiate antidiarrheals, orbifloxacin, oxacillinsodium, oxazepam, oxfendazole, oxibutynin chloride, oxymorphone HCl,oxytretracycline, oxytocin, pamidronate disodium, pancreplipase,pancuronium bromide, paromomycin sulfate, parozetine HCl, pencillamine,general information penicillins, penicillin G, penicillin V potassium,pentazocine, pentobarbital sodium, pentosan polysulfate sodium,pentoxifylline, pergolide mesylate, phenobarbital, phenoxybenzamine HCl,pheylbutazone, phenylephrine HCL, phenypropanolamine HCl, phenyloinsodium, pheromones, parenteral phosphate, phytonadione/vitamin K-1,pimobendan, piperazine, pirlimycin HCL, piroxicam, polysulfatedglycosaminoglycan, ponazuril, potassium chloride, pralidoxime chloride,praziquantel, prazosin HCl, prednisolone/prednisone, primidone,procainamide HCl, procarbazine HCl, prochlorperazine, propanthelinebromide, propionibacterium acnes injection, propofol, propranolol HCl,protamine sulfate, pseudoephedrine HCl, psyllium hydrophilic mucilloid,pyrantel pamoate, pyridostigmine bromide, pyrilamine maleate,pyrimethamine, quinacrine HCl, quinidine, ranitidine HCl, rifampin,s-adenosyl-methionine (SAMe), saline/hyperosmotic laxative, selamectin,selegiline HCL/l-deprenyl, sertraline HCl, sevelamer HCl, sevoflurane,silymarin/milk thistle, sodium bicarbonate, sodium polystyrenesulfonate, sodium stibogluconate, sodium sulfate, sodum thiosulfate,somatotropin, sotalol HCl, spectinomycin HCl, spironolactone,stanozolol, streptokinase, streptozocin, succimer, succinylcholinechloride, sucralfate, sufentanil citrate, sulfachlorpyridazine sodium,sulfadiazine/trimethroprim, sulfamethoxazole/trimethoprim,sulfadimentoxine, sulfadimethoxine/ormetoprim, sulfasalazine, taurine,tepoxaline, terbinafline HCl, terbutaline sulfate, testosterone,tetracycline HCl, thiabendazole, thiacetarsamide sodium, thiamine HCl,thioguanine, thiopental sodium, thiotepa, thyrotropin, tiamulin,ticarcilin disodium, tiletamine HCl/zolazepam HCl, tilmocsin, tiopronin,tobramycin sulfate, tocamide HCl, tolazoline HCl, telfenamic acid,topiramate, tramadol HCl, trimcinolone acetonide, trientine HCl,trilostane, trimepraxine tartrate w/prednisolone, tripelennamine HCl,tylosin, urdosiol, valproic acid, vanadium, vancomycin HCl, vasopressin,vecuronium bromide, verapamil HCl, vinblastine sulfate, vincristinesulfate, vitamin E/selenium, warfarin sodium, xylazine HCl, yohimbineHCl, zafirlukast, zidovudine (AZT), zinc acetate/zinc sulfate,zonisamide and mixtures thereof.

In one embodiment of the invention, other arylpyrazole compounds such asphenylpyrazoles, as described above in the Background (e.g. fipronil),are known in the art and are suitable for combination with the1-aryl-5-alkyl pyrazole compounds of the invention. Examples of sucharylpyrazole compounds include but are not limited to those described inU.S. Pat. Nos. 6,001,384; 6,010,710; 6,083,519; 6,096,329; 6,174,540;6,685,954 and 6,998,131—each assigned to Merial, Ltd., Duluth, Ga.).

In another embodiment of the invention, nodulisporic acid and itsderivatives (a class of known acaricidal, anthelminitic, anti-parasiticand insecticidal agents) can be added to the compositions of theinvention. These compounds are used to treat or prevent infections inhumans and animals and are described, for example, in U.S. Pat. Nos.5,399,582 and 5,962,499. The composition can include one or more of theknown nodulisporic acid derivatives in the art, including allstereoisomers, such as those described in the literature cited above.

In another embodiment of the invention, one or more macrocycliclactones, which act as an acaricide, anthelmintic agent and insecticide,can be added to the compositions of the invention. The macrolides arewell-known in the art (see e.g. Macrolides—Chemistry, pharmacology andclinical uses—edited by Bryskier et al., publ. by Arnette Blackwell,(1993)) and include but are not limited to 12-membered ring macrolides(e.g. methymycin, neomethymycin, YC-17, litorin); 14-membered ringmacrolides (e.g. erythromycin A-F, oleandomycin, sporeamicin,roxithromycin, dirithromycin, flurithromycin, clarithromycin, davercin);15-membered ring macrolides (e.g. azithromycin); 16-membered ringmacrolides (e.g. josamycin, kitasamycin, spiramycin, midecamycin,rokitamycin, miokamicin) and 17-membered ring macrolides (e.g.lankadicin).

The macrocyclic lactones also include, but are not limited to,avermectins, such as abamectin, dimadectin, doramectin, emamectin,eprinomectin, ivermectin, latidectin, lepimectin, selamectin andmilbemycins, such as milbemectin, milbemycin D, moxidectin andnemadectin. Also included are the 5-oxo and 5-oxime derivatives of saidavermectins and milbemycins. Examples of combinations of arylpyrazolecompounds with macrocyclic lactones include but are not limited to thosedescribed in U.S. Pat. Nos. 6,426,333; 6,482,425; 6,962,713 and6,998,131—each assigned to Merial, Ltd., Duluth, Ga.

The macrocyclic lactone compounds are known in the art and can easily beobtained commercially or through synthesis techniques known in the art.Reference is made to the widely available technical and commercialliterature. For avermectins, ivermectin and abamectin, reference may bemade, for example, to the work “Ivermectin and Abamectin”, 1989, by M.H. Fischer and H. Mrozik, William C. Campbell, published by SpringerVerlag., or Albers-Schönberg et al. (1981), “Avermectins StructureDetermination”, J. Am. Chem. Soc., 103, 4216-4221. For doramectin,“Veterinary Parasitology”, vol. 49, No. 1, July 1993, 5-15 may beconsulted. For milbemycins, reference may be made, inter alia, to DaviesH. G. et al., 1986, “Avermectins and Milbemycins”, Nat. Prod. Rep., 3,87-121, Mrozik H. et al., 1983, Synthesis of Milbemycins fromAvermectins, Tetrahedron Lett., 24, 5333-5336, U.S. Pat. No. 4,134,973and EP 0 677 054.

Macrocyclic lactones are either natural products or are semi-syntheticderivatives thereof. The structure of the avermectins and milbemycinsare closely related, e.g., by sharing a complex 16-membered macrocycliclactone ring; milbemycins lack the glycosidic moiety of the avermectins.The natural product avermectins are disclosed in U.S. Pat. No. 4,310,519to Albers-Schönberg et al., and the 22,23-dihydro avermectin compoundsare disclosed in Chabala et al., U.S. Pat. No. 4,199,569. Mention isalso made of Kitano, U.S. Pat. No. 4,468,390, Beuvry et al., U.S. Pat.No. 5,824,653, EP 0 007 812 A1, U.K. Patent Specification 1 390 336, EP0 002 916, and Ancare New Zealand Patent No. 237 086, inter alia.Naturally occurring milbemycins are described in Aoki et al., U.S. Pat.No. 3,950,360 as well as in the various references cited in “The MerckIndex” 12^(th) ed., S. Budavari, Ed., Merck & Co., Inc. WhitehouseStation, N.J. (1996). Latidectin is described in the “InternationalNonproprietary Names for Pharmaceutical Substances (INN)”, WHO DrugInformation, vol. 17, no. 4, pp. 263-286, (2003). Semisyntheticderivatives of these classes of compounds are well known in the art andare described, for example, in U.S. Pat. Nos. 5,077,308, 4,859,657,4,963,582, 4,855,317, 4,871,719, 4,874,749, 4,427,663, 4,310,519,4,199,569, 5,055,596, 4,973,711, 4,978,677, 4,920,148 and EP 0 667 054.

In another embodiment of the invention, the class of acaricides orinsecticides known as insect growth regulators (IGRs) can also be addedto the compositions of the invention. Compounds belonging to this groupare well known to the practitioner and represent a wide range ofdifferent chemical classes. These compounds all act by interfering withthe development or growth of the insect pests. Insect growth regulatorsare described, for example, in U.S. Pat. Nos. 3,748,356; 3,818,047;4,225,598; 4,798,837; 4,751,225, EP 0 179 022 or U.K. 2 140 010 as wellas U.S. Pat. Nos. 6,096,329 and 6,685,954 (both assigned to Merial Ltd.,Duluth, Ga.). Examples of IGRs suitable for use include but are notlimited to methoprene, pyriproxyfen, hydroprene, cyromazine, fluazuron,lufenuron, novaluron, pyrethroids, formamidines and1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea.

An anthelmintic agent that can be combined with the compound of theinvention to form a composition can be a benzenedisulfonamide compound,which includes but is not limited to clorsulon; or a cestodal agent,which includes but is not limited to praziquantel, pyrantel or morantel.

An antiparasitic agent that can be combined with the compound of theinvention to form a composition can be a biologically active peptide orprotein including, but not limited to, depsipeptides, which act at theneuromuscular junction by stimulating presynaptic receptors belonging tothe secretin receptor family resulting in the paralysis and death ofparasites. In one embodiment of the depsipeptide, the depsipeptide isemodepside.

An insecticidal agent that can be combined with the compound of theinvention to form a composition can be a spinosyn (e.g. spinosad) or asubstituted pyridylmethyl derivative compound such as imidacloprid.Agents of this class are described above, and for example, in U.S. Pat.No. 4,742,060 or in EP 0 892 060. It would be well within the skilllevel of the practitioner to decide which individual compound can beused in the inventive formulation to treat a particular infection of aninsect.

An insecticidal agent that can be combined with the compound of theinvention to form a composition can be a semicarbazone, such asmetaflumizone (BAS3201). Metaflumizone is a relatively safe compound(oral LD50>5,000 mg/kg) with known activity on various Lepidoptera croppest species.

Where appropriate the anthelmintic, antiparasitic and insecticial agentmay also be selected from the group of compounds described above assuitable for agrochemical use.

In general, the additional pesticidal agent is included in a dose ofbetween about 0.1 μg and about 10 mg. In one embodiment of theinvention, the additional pesticidal agent is included in a dose ofbetween about 1 μg and about 10 mg. In another embodiment of theinvention, the additional pesticidal agent is included in a dose ofabout 5 to about 200 μg/kg of weight of animal. In yet anotherembodiment of the invention, the additional pesticidal agent is includedin a dose between about 0.1 to about 10 mg/kg of weight of animal. Instill another embodiment of the invention, the additional pesticidalagent is included in a dose between about 0.5 to 50 mg/kg.

The proportions, by weight, of the 1-aryl-5-alkyl pyrazole compound andthe additional pesticidal agent are for example between about 5/1 andabout 10,000/1. However, one of ordinary skill in the art would be ableto select the appropriate ratio of 1-aryl-5-alkyl pyrazole compound andthe additional pesticidal agent for the intended host and use thereof.

Method of Synthesizing the Compounds of the Invention

The compounds of formula (I) may be prepared by the application oradaptation of known methods (i.e. methods heretofore used or describedin the chemical literature): generally pyrazole ring formation followedwhere necessary by changing substituents; or methods described in one ormore of WO 98/28278 (U.S. Pat. No. 6,350,771), WO 87/03781 (U.S. Pat.No. 5,232,940) and EP 780 378 (U.S. Pat. No. 5,817,688). It will beappreciated by persons skilled in the art that, within aspect of theprocesses described; the order of the synthetic steps employed may bevaried and will depend inter alia on factors such as the nature of otherfunctional groups present in a particular substrate, the availability ofkey intermediates, and the protecting group strategy (if any) to beadopted (see e.g. “Protective Groups in Organic Synthesis (ThirdEdition)”, eds. Greene and Wuts, Wiley-Interscience, (1999)). Clearly,such factors will also influence the choice of reagents for use in thesaid synthetic steps.

In one embodiment of the invention, compounds of formula (I) wherein R₃is halomethyl are formed by reaction of the corresponding compounds offormula (I) in which R₃ is hydroxymethyl with halogenating reagents,more specifically brominating reagents such as a mixture of bromine orN-bromosuccinimide and triphenylphosphine, hydrobromic acid; orfluorinating reagents such as dimethylaminosulfur trifluoride,diethylaminosulfur trifluoride (DAST™) or bis(2-methoxyethyl)aminosulfurtrifluoride (Deoxofluor™). The reaction is usually performed in asolvent such as methylene chloride, chloroform and generally attemperatures between −100° C. and 40° C. A summary of such methods isfound in Comprehensive Organic Transformations, VCH Publishers, 1989, R.C. Larock, pp. 353-360.

In another embodiment of the invention, compounds of formula (I) whereinR₃ is methyl are formed by reaction of the corresponding compounds offormula (I) in which R₃ is halomethyl with reducing reagents such asdiisobutyl aluminum hydride (DIBAL-H), lithium aluminum hydride, sodiumborohydride or lithium tri-sec-butyl borohydride (L-Selectride™). In oneembodiment of the process, the reducing agent is L-Selectride™. Thereaction is usually performed in a solvent such as dialkyl ether (e.g.diethyl ether), tetrahydrofuran (THF) and generally at temperaturesbetween about −100° C. and about 40° C. A summary of such methods isfound in Comprehensive Organic Transformations, VCH Publishers, 1989, R.C. Larock, pp. 18-21.

According to methods referred to in the chemical literature and in EP780 378, intermediates of formula (I) wherein R₃ is hydroxymethyl areformed by reaction of the corresponding compounds of formula (I) inwhich R₃ is formyl with hydride reagents such as diisobutyl aluminumhydride (DIBAL-H), lithium aluminum hydride, sodium borohydride orlithium tri-sec-butyl borohydride (L-Selectride™). In one embodiment ofthe process, the hydride agent is sodium borohydride. The reaction maybe performed in a solvent such as dialkyl ether (e.g. diethyl ether),tetrahydrofuran (THF), or a hydrocarbon (e.g. hexane or toluene) ormixtures thereof. A temperature of from about −100 to about the refluxtemperature of the solvent system is generally used. In one embodimentof the process, the temperature is between about 0° C. to about roomtemperature. A summary of such methods is found in Comprehensive OrganicTransformations, VCH Publishers, 1989, R. C. Larock, pp. 527-535.Compounds of formula (I) where R₃ is hydroxymethyl are novel,specifically when Z in this formula (I) is C—F, and constitute a furtherembodiment of the invention.

According to methods described in EP 780 378, intermediates of formula(I) wherein R₃ is formyl are formed by oxidative cleavage of the alkenemoiety of a compound of formula (II)

wherein R^(A) is selected from alkylcarbonyl, alkoxycarbonyl, cyano andnitro to form a compound of formula (IIa):

In another embodiment of the process, R^(A) is selected from C₁-C₄alkylcarbonyl, C₁-C₄ alkoxycarbonyl, cyano and nitro. Such atransformation is well known to those skilled in the art and can berealized for example with ozone, potassium permanganate, sodiummetaperiodate. The process may be carried out optionally in a solventsuch as methylene chloride, diethylether, chloroform and generally attemperatures between about −100 and about 100° C. A summary of suchmethods is found in Comprehensive Organic Transformations, VCHPublishers, 1989, R. C. Larock, pp. 595-596.

Compound of formula (II) may be prepared by dehydrohalogenation of acompound of formula (III) wherein “halo” represents halogen.

This can be effected by reaction of formula (III) compounds with basessuch as triethylamine, sodium hydroxide, potassium hydroxide, lithiumdiisopropylamide or 1,8-diazabicyclo-[5.4.0]-undec-7-ene (DBU). In oneembodiment of the process, the base is DBU. The reaction is carried outoptionally with an organic solvent such as dichloromethane,diethylether, tetrahydrofuran, or toluene, and generally between about−100 and about 100° C. depending on the base used. A summary of suchmethods is found in Comprehensive Organic Transformations, VCHPublishers, 1989, R. C. Larock, pp. 131-132.

Certain compounds of formula (II) and formula (III) are novel,specifically when Z in those formula (II) and (III) is C—F, and as suchconstitute a further embodiment of the invention. Compounds of formula(III) can be produced from compounds of formula (I), wherein R₃ is NH₂(formula (V)):

with an olefin of formula (IV):

The process is effected by reaction of a compound of formula (I),wherein R₃ is replaced by NH₂, in the presence of an alkylnitrite andCopper (II) halide, for example as described in J. Org. Chem., 1977, 42(14), 2431. Those skilled in the art will recognize this as a Meerweinarylation reaction, as reviewed in Org. React., 1976, 24, 225-259. Theprocess is generally carried out in a mixture of the olefin and a commonorganic solvent, such as acetonitrile and at a temperature from about−50 and about 100° C. In one embodiment of the process, the temperatureis about room temperature.

The compounds of formula (I) in which R₃ is replaced by NH₂ may beprepared by methods described in one or more of the following: WO94/21606, WO 93/06089, WO 87/03781; EP 295 117, EP 234 119; U.S. Pat.No. 5,232,940; or by methods known to the skilled in the art. Certaincompounds of formula (I) wherein R₃ is NH₂ are novel, specifically whenZ in this formula (I) is C—F, and as such constitute a furtherembodiment of the invention.

The synthesis of higher oxidation states of compounds of formula (I),i.e. compounds in which m is 1 or 2, can be achieved by oxidation of thecorresponding precursor compound of formula (Ibis).

wherein m is 0 or 1, using conventional oxidizers known in the art.

In one embodiment of the invention, a general reaction scheme forsynthesizing the compound of formula (I) can be described as follows:

In one embodiment of the present invention, compounds of formula (I)wherein R₃ is ethyl may be prepared by the reaction of the correspondingcompounds of formula (I) in which R₃ is replaced by vinyl by catalytichydrogenation, in the presence of a hydrogen source (for examplehydrogen gas, sodium hydride, lithium aluminum hydride or sodiumborohydride) and one or more catalytic metals (such as cobalt, nickel,palladium, platinum, ruthenium and rhodium). The reaction is generallyperformed in a solvent such as an alcohol (e.g. ethanol or methanol) andat temperatures between about −100° C. and about 200° C. A summary ofsuch methods is found in Comprehensive Organic Transformations, VCHPublishers, 1989, R. C. Larock, pp. 6-8.

Compounds of formula (I) wherein R₃ is replaced by vinyl may be preparedby reaction of the corresponding compounds of formula (I) in which R₃ isreplaced by halogen (e.g. chlorine, iodine or bromine), withvinyltributyltin, in the presence or absence of a base (for examplecesium fluoride or cesium carbonate) and with a palladium catalyst suchas tetrakis(triphenylphosphine)palladium. The reaction is generallyperformed in a solvent such an alcohol (e.g. ethanol), a dialkyl ether(e.g. diethyl ether), tetrahydrofuran (THF), or dioxane and attemperatures between about 10° C. and about 300° C.

The reaction may be heated in a sealed tube in a microwave. Thistransformation is known as a Stille Cross-Coupling reaction and asummary of such methods is found in “Metal-Catalyzed Cross CouplingReactions”, Wiley-VCH publishers, 1998, F. Diedrich and P. J. Stang,chapter 4 by T. N. Mitchell.

Alternative Method of Synthesizing the Compounds of the Invention

Another embodiment of the second aspect of the invention provides aprocess of making 1-aryl-5-alkyl pyrazole compound of formula (I):

wherein:

-   -   R₁ is hydrogen, cyano, halogen, R₈, formyl, —C(O)R₈, —C(O)OR₈,        —C(O)NR₉R₁₀, or —C(S)NH₂;    -   R₂ is R₈ or —S(O)_(m)R₁₁;    -   R₃ is methyl, ethyl or C₁-C₄ haloalkyl;    -   R₄, R₅ and R₇ are independently hydrogen, halogen, alkyl,        haloalkyl, cyano or nitro;    -   R₆ is halogen, alkyl, haloalkyl, alkoxy, haloalkyloxy, cyano,        nitro, —C(O)R₁₂, —S(O)_(n)R₁₂ or SF₅;    -   Z is a nitrogen atom or C—R₁₃;    -   R₈ is alkyl, haloalkyl, cycloalkyl or halocycloalkyl;    -   R₉ is hydrogen, alkyl, haloalkyl or alkoxy;    -   R₁₀ is hydrogen, alkyl, haloalkyl or alkoxy;    -   R₁₁ is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl or cycloalkyl;    -   R₁₂ is alkyl or haloalkyl;    -   R₁₃ is hydrogen, halogen, cyano, nitro, alkyl, haloalkyl, alkoxy        or haloalkoxy;    -   m is 0, 1 or 2; and    -   n is 0, 1 or 2; or    -   a salt thereof

which comprises:

(i) reacting a compound of formula (II):

-   -   with a compound of formula R₂—Y to produce a compound of formula        (III):

-   -   wherein

R₂ is R₈, —O—R₈ or NR₉R₁₀

R₂, R₃ R₈, R₉ and R₁₀ are as defined above and

Y is a leaving group such as halogen

(the di-keto compounds of formula (II) and formula (III) may also existin their enol form);

(ii) reacting the compound of formula (III) with a compound of formula(Va) or salt thereof:

-   -   to produce a compound of formula (VI):

-   -   wherein Ra, R₂, R₃, R₄, R₅, R₆, R₇ and Z are as defined below;        and

(iii) deesterification of the ester moiety of formula (VI), whereinR_(a) is equal to O—R₈ and R₈ is defined above, by base catalyzedhydrolysis and subsequent acidification to form the compoundcorresponding to formula (VIa):

and

(iv) derivatizing the compound of formula (VIa) to produce the compoundof formula (I).

In a first embodiment of the second aspect of the invention, step (iv)is selected from the group consisting of:

-   (a) a decarboxylation step;-   (b) reacting the compound of formula (VIa) or formula (VI), wherein    R_(a) is equal to halogen such as chloride, with HNR₉R₁₀ wherein R₉    and R₁₀ are as defined above-   (c) (i) reduction of the —CO₂H moiety to —CH₂OH;    -   (ii) an oxidation step to form —CHO;    -   (iii) reaction with a Grignard reagent (R₈—Mg-halogen);    -   (iv) an additional oxidation step; or    -   (ia) reacting the —CO₂H moiety of (VIa) with an agent to form        the corresponding N-methoxy-N-methyl amide (Weinreb amide); and    -   (iia) reaction with a Grignard reagent (R₈—Mg-halogen) or an        organolithium reagent (R₈—Li).        General ketone formation from Weinreb amides is described in        March's Advanced Organic Chemistry—Reactions, Mechanisms and        Structure (6^(th) Edition), ed. Michael B. Smith and Jerry        March, Wiley Interscience (John Wiley & Sons, Inc.), page 1448,        (2007).

In a second embodiment of the second aspect of the invention, step (iv)is a decarboxylation of the compound of formula (IIa) to form thecompound of formula (I) wherein R₁ is hydrogen.

In a third embodiment of the second aspect of the invention, step (iv)is a decarboxylation step followed by a halogenation step to produce thecompound of formula (I) wherein R₁ is halogen. An example of a generalprocess for decarboxylation followed by halogenations is Morimoto et al,“Synthesis of Halosulfuron-methyl via Selective Chlorination at 3-and/or 5-position of Pyrazole-4-carboxylates”, J. Het. Chem., 34:537-540 (1997).

In a fourth embodiment of the second aspect of the invention, step (iv)comprises reacting the compound of formula (VIa) with HNR₉R₁₀, inpresence of coupling agents such as dicyclohexylcarbodiimide and thelike, wherein R₉ and R₁₀ are as defined above, to form a compound offormula (I) where R₁ is CONR₉R₁₀ A general description of thistransformation is described in March's Advanced OrganicChemistry—Reactions, Mechanisms and Structure (6^(th) Edition), ed.Michael B. Smith and Jerry March, Wiley Interscience (John Wiley & Sons,Inc.), page 1430-1434 (16-74—Acylation of Amines by CarboxylicAcids—Amino-de-hydroxylation), (2007).

In a fifth embodiment of the second aspect of the invention, step (iv)comprises reacting the compound of formula (VI), wherein Ra is equal tohalogen such as chloride, with HNR₉R₁₀, wherein R₉ and R₁₀ are asdefined above, to form a compound of formula (I) where R₁ is CONR₉R₁₀ Ageneral description of this transformation is described in March'sAdvanced Organic Chemistry—Reactions, Mechanisms and Structure (6^(th)Edition), ed. Michael B. Smith and Jerry March, Wiley Interscience (JohnWiley & Sons, Inc.), page 1427-1429 (16-72—Acylation of Amines by AcylHalides—Amino-de-halogenation), (2007).

In a sixth embodiment of the second aspect of the invention, step (iv)comprises reacting the compound of formula (VIa) or formula (VI),wherein R_(a) is equal to halogen such as chloride, with HNR₉R₁₀,wherein R₉ and R₁₀ are both hydrogen, to form a compound of formula (I),where R₁ is CONR₉R₁₀, and is further reacted with a dehydrating agentsuch as thionyl chloride, oxalyl chloride and the like, to form thecompound of formula (I) wherein R₁ is cyano A general description ofthis transformation is described in March's Advanced OrganicChemistry—Reactions, Mechanisms and Structure (6^(th) Edition), ed.Michael B. Smith and Jerry March, Wiley Interscience (John Wiley & Sons,Inc.), page 1549-1550 (17-30—Dehydration of UnsubstitutedAmides—N,N-dihydro-C-oxo-bielimination), (2007).

In a seventh embodiment of the second aspect of the invention, step (iv)comprises reacting the amide of formula (VI) wherein R_(a) is equal toHNR₉R₁₀ and R₉ and R₁₀ are both hydrogen above with2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide(known as Lawesson's reagent) and related reagents to form the thioamideof formula (I) wherein R₁ is C(S)NH₂ A general description of thistransformation is described in March's Advanced OrganicChemistry—Reactions, Mechanisms and Structure (6^(th) Edition), ed.Michael B. Smith and Jerry March, Wiley Interscience (John Wiley & Sons,Inc.), page 1277-1278 (16-11—The Addition of H₂S and Thiols to CarbonylCompounds—O-Hydro-C-mercapto-addition), (2007).

In an eighth embodiment of the second aspect of the invention, step (iv)comprises: (i) reduction of the —CO₂H moiety in the compound of formula(VIa) to —CH₂OH; (ii) oxidation of the —CH₂OH moiety to form a —CHOmoiety in the compound of formula (IIa); (iii) reaction of the —CHOmoiety with a Grignard reagent (R₈—Mg-halogen) or an organolithiumreagent; and (iv) an additional oxidation step.

In a ninth embodiment of the second aspect of the invention, step (iv)comprises: (i) reduction of the —CO₂H moiety in the compound of formula(VIa) to —CH₂OH; (ii) oxidation of the —CH₂OH moiety to form a —CHOmoiety in the compound of formula (IIa); (iii) reaction of the —CHOmoiety with a Grignard reagent (R₈—Mg-halogen) or an organolithiumreagent; and (iv) additional reduction steps of the hydroxyl moiety toyield the compound of formula (I) wherein R₁ is R₈ is formed

The alternative process of making 1-aryl-5-alkyl pyrazole compound offormula (I) differs with the process described above in that the latterprocess derivatizes an aryl pyrazole compound to form the alkyl moietiesat R₃. However, the alternative process is directed toward the formationof a pyrazole ring which already has the alkyl moieties of R₃ attached.The subsequent process steps involve the derivatization of the moiety atthe R₁ position. The described invention is a more elegant process thatuses fewer process steps which require handling the larger aryl pyrazolestructure, i.e. derivatization is mostly achieved by working withsmaller sized compounds which are then later combined to form the largeraryl pyrazole structure.

Alternatively, a tenth embodiment of the second aspect of the inventionprovides a process of making 1-aryl-3,4,5-trisubstituted pyrazolecompound of formula (I):

(i) reacting the compound of formula (III) with hydrazine or saltthereof to form the compound of formula (IV):

-   -   wherein R_(a), R₂ and R₃ have the above meanings; and

(iii) reacting the compound of formula (IV) with the compound of formula(Vb) wherein L is a leaving group to form the compound of formula (VI):

-   -   wherein R_(a), R₂, R₃, R₄, R₅, R₆, R₇ and Z have the above        meanings and L is a leaving group (suitable leaving groups        include but are not limited to halogen, trifluoromethane        sulfonyl, methanesulfonyl, toluenesulfonyl and the like);

(iv) optionally, subjecting the compound of formula (VI) to functionalgroup modification with the —C(═O)R_(a) moiety.

An eleventh embodiment of the second aspect of the invention is that theprocess for preparing the 1-aryl-3,4,5-trisubstituted pyrazoles offormula (I) produces high yield. In one embodiment of the third aspectof the invention, the yield is from about 55% to about 95% (for bothalternative processes of the invention)

A twelfth embodiment of the second aspect of the invention of theinvention is to provide a process for preparing1-aryl-3,4,5-trisubstituted pyrazoles from 1,3-diketones with excellentregioselectivity. In one embodiment of the fourth aspect of theinvention, the regioselectivity of the formation of the compound offormula (VI) from the compound of formula (III) is from about 70% toabout +99%

A thirteenth embodiment of the second aspect of the invention is tofurther derivatize the compounds of formula (I) by functional grouptransformation.

A fourteenth embodiment of the second aspect of the invention, thefunctional group transformation correspond to step (iv) of the firstaspect of the invention.

A fifteenth embodiment of the second aspect of the invention, where R₁is a —C(O)OR₈ is further derivatized to form R₁ as CN via a four stepprocess wherein step one comprises reacting a compound of formula (VIb)with a base and subsequent acidification to form a compound of formula(VIa), step two comprises reacting a compound of formula (VIa) and ahalogenating agent to form a compound of formula (VIc), step threecomprises reacting a compound of formula (VIc) with an amino base toform the compound of formula (VId) and step three comprises reacting acompound of formula (VId) with a dehydrating agent such as SOCl₂ to formthe compound of formula (I). One example of this transformation isdepicted in the reaction scheme below:

A sixteenth embodiment of the second aspect of the invention, where R₂is —S(O)_(m)R₁₁ and m is 0 or 1, the sulfur is oxidized to form—S(O)_(m)R₇ where m is 1 and 2 respectively.

A seventeenth aspect of the invention is to prepare 1,3-dicarbonylcompounds by reacting a compound of formula (II) with a compound R₂—Y toform a compound of formula (III)—see equation below:

wherein R_(a), R₂, R₃ and Z have the above meanings. (The di-ketocompounds of formula (II) and formula (III) may also exist in their enolform). Advantageously, R₂ is —S(O)_(m)R₁₁.

An eighth aspect of the invention is to prepare compounds of formula(IV) by reacting a compound of formula (III) with a hydrazine to formthe compounds of formula (IV)—see equation below:

wherein R_(a), R₂, and R₃ have the above meanings.

The acids, bases and solvents and the individual process steps such asalkylation, Grignard reaction/reagents, halogenation and oxidation usedin the invention will be apparent to those of ordinary skill in the art(e.g. Vogel's Textbook of Practical Organic Chemistry (Fifth Edition),Furniss et al., Longman Scientific & Technical (1989); Protective Groupsin Organic Synthesis (Third Edition), Greene & Wuts, Wiley Interscience(1999); March's Advanced Organic Chemistry: Reactions, Mechanisms, andStructure (6^(th) Edition), March & Smith, Wiley, (2007); AdvancedOrganic Chemistry (Part A—Structure and Mechanisms—4^(th) Edition),Carey & Sundberg, Springer Science (2000); Advanced Organic Chemistry(Part B—Reaction and Synthesis—4^(th) Edition), Carey & Sundberg,Springer Science (2001); Strategic Applications of Named Reactions inOrganic Synthesis, Kurti and Czako, Academic Press (2005).

Appropriate solvents for the process of reacting the compound of formula(II) with the compound of formula R₂—Z to form the compound of formula(III) include but are not limited to tetrahydrofuran, dimethylformamide,halogenated hydrocarbons or mixtures thereof.

Appropriate bases for the process of reacting the compound of formula(II) with the compound of formula R₂—Z to form the compound of formula(III) include but are not limited to metal hydride, metalbis(trimethylsilyl)amide, alkylamines such as trialkylamine, hydroxidessuch as metal hydroxides and alkoxides such as metal alkoxides.

Appropriate temperatures for the process of reacting the compound offormula (II) with the compound of formula R₂—Z to form the compound offormula (III) range from about −50 to about 50° C.

Appropriate solvents for the process of reacting the compound of formula(IV) with the compound of formula (V), or a salt thereof, to form thecompound of formula (I) include but are not limited to alcohols such asmethanol, ethanol, propanol, isopropanol, butanol; water;tetrahydrofuran; dimethylamino formate; halogenated hydrocarbons ormixtures thereof.

Appropriate additives for the process of reacting the compound offormula (IV) with the compound of formula (V), or a salt thereof, toform the compound of formula (I) include but are not limited to acidiccompounds such as hydrogen halide, sulfuric acid, nitric acid andcarboxylic acid.

Appropriate temperatures for the process of reacting the compound offormula (IV) with the compound of formula (V), or a salt thereof, toform the compound of formula (I) range from about −20 to about 100° C.

Method of Treatment, Dosage Ranges and Routes of Administration

The invention is also directed toward a method of treating an animal(e.g. a mammal or bird), against ectoparasitic infection byadministering an ectoparasiticidally effective amount of the compositionof the invention. Mammals which can be treated include but are notlimited to humans, cats, dogs, cattle, chickens, cows, deer, goats,horses, llamas, pigs, sheep and yaks. In one embodiment of theinvention, the mammals treated are humans, cats or dogs.

In another embodiment for treatment against ectoparasites, theectoparasite is one or more insect or arachnid including those of thegenera Ctenocephalides, Rhipicephalus, Dermacentor, Ixodes, Boophilus,Ambylomma, Haemaphysalis, Hyalomma, Sarcoptes, Psoroptes, Otodectes,Chorioptes, Hypoderma, Damalinia, Linognathus, Haematopinus, Solenoptes,Trichodectes, and Felicola.

In another embodiment for the treatment against ectoparasites, theectoparasite is from the genera Ctenocephalides, Rhipicephalus,Dermacentor, Ixodes and/or Boophilus. The ectoparasites treated includebut are not limited to fleas, ticks, mites mosquitoes, flies, lice,blowfly and combinations thereof. Specific examples include but are notlimited to cat and dog fleas (Ctenocephalides felis, Ctenocephalides sp.and the like), ticks (Rhipicephalus sp., Ixodes sp., Dermacentor sp.,Amblyoma sp. and the like), and mites (Demodex sp., Sarcoptes sp.,Otodectes sp. and the like), lice (Trichodectes sp., Cheyletiella sp.,Lignonathus sp., and the like), mosquitoes (Aedes sp., Culex sp.,Anopheles sp., and the like) and flies (Hematobia sp., Musca sp.,Stomoxys sp., Dematobia sp., Cochliomyia sp., and the like). In yetanother embodiment for the treatment against ectoparasites, theectoparasite is a flea and/or tick.

Additional examples of ectoparasites include but are not limited to thetick genus Boophilus, especially those of the species microplus (cattletick), decoloratus and annulatus; myiases such as Dermatobia hominis(known as Berne in Brazil) and Cochliomyia hominivorax (greenbottle);sheep myiases such as Lucilia sericata, Lucilia cuprina (known asblowfly strike in Australia, New Zealand and South Africa). Fliesproper, namely those whose adult constitutes the parasite, such asHaematobia irritans (horn fly); lice such as Linognathus vitulorum,etc.; and mites such as Sarcoptes scabici and Psoroptes ovis. The abovelist is not exhaustive and other ectoparasites are well known in the artto be harmful to animals and humans. These include, for examplemigrating dipterous larvae.

When an anthelmintic agent is added to the composition of the invention,the composition can also be used to treat against endoparasites such asthose helminths selected from the group consisting of Anaplocephala,Ancylostoma, Anecator, Ascaris, Capillaria, Cooperia, Dipylidium,Dirofilaria, Echinococcus, Enterobius, Fasciola, Haemonchus,Oesophagostumum, Ostertagia, Toxocara, Strongyloides, Toxascaris,Trichinella, Trichuris, and Trichostrongylus.

In addition with or without the addition of other pesticidal agentsadded to the composition, the invention can also be used to treat otherpests which include but are not limited to pests:

-   (1) from the order Isopoda, for example Oniscus asellus,    Armadillidium vulgare and Porcellio scaber;-   (2) from the order Diplopoda, for example Blaniulus guttulatus;-   (3) from the order Chilopoda, for example Geophilus carpophagus and    Scutigera spp.;-   (4) from the order Symphyla, for example Scutigerella immaculata;-   (5) from the order Thysanura, for example Lepisma saccharina;-   (6) from the order Collembola, for example Onychiurus armatus;-   (7) from the order Orthoptera, for example Acheta domesticus,    Gryllotalpa spp., Locusta migratoria migratorioides, Melanoplus spp.    and Schistocerca gregaria;-   (8) from the order Blattaria, for example Blatta orientalis,    Periplaneta americana, Leucophaea maderae and Blattella germanica;-   (9) from the order Dermaptera, for example Forficula auricularia;-   (10) from the order Isoptera, for example Reticulitermes spp.;-   (11) from the order Phthiraptera, for example Pediculus humanus    corporis, Haematopinus spp., Linognathus spp., Trichodectes spp. and    Damalinia spp.;-   (12) from the order Thysanoptera, for example Hercinothrips    femoralis, Thrips tabaci, Thrips palmi and Frankliniella    accidentalis;-   (13) from the order Heteroptera, for example Eurygaster spp.,    Dysdercus intermedius, Piesma quadrata, Cimex lectularius, Rhodnius    prolixus and Triatoma spp.;-   (14) from the order Homoptera, for example Aleurodes brassicae,    Bemisia tabaci, Trialeurodes vaporariorum, Aphis gossypii,    Brevicoryne brassicae, Cryptomyzus ribis, Aphis fabae, Aphis pomi,    Eriosoma lanigerum, Hyalopterus arundinis, Phylloxera vastatrix,    Pemphigus spp., Macrosiphum avenae, Myzus spp., Phorodon humuli,    Rhopalosiphum padi, Empoasca spp., Euscelis bilobatus, Nephotettix    cincticeps, Lecanium corni, Saissetia oleae, Laodelphax striatellus,    Nilaparvata lugens, Aonidiella aurantii, Aspidiotus hederae,    Pseudococcus spp. and Psylla spp.;-   (15) from the order Lepidoptera, for example Pectinophora    gossypiella, Bupalus piniarius, Chematobia brumata, Lithocolletis    blancardella, Hyponomeuta padella, Plutella xylostella, Malacosoma    neustria, Euproctis chrysorrhoea, Lymantria spp., Bucculatrix    thurberiella, Phyllocnistis citrella, Agrotis spp., Euxoa spp.,    Feltia spp., Earias insulana, Heliothis spp., Helicoverpa spp.,    Mamestra brassicae, Panolis flammea, Spodoptera spp., Trichoplusia    ni, Carpocapsa pomonella, Pieris spp., Chilo spp., Pyrausta    nubilalis, Ephestia kuehniella, Galleria mellonella, Tineola    bisselliella, Tinea pellionella, Hofmannophila pseudospretella,    Cacoecia podana, Capua reticulana, Choristoneura fumiferana, Clysia    ambiguella, Homona magnanima, Tortrix viridana and Cnaphalocerus    spp.;-   (16) from the order Coleoptera, for example Anobium punctatum,    Rhizopertha dominica, Bruchidius obtectus, Acanthoscelides obtectus,    Hylotrupes bajulus, Agelastica alni, Leptinotarsa decemlineata,    Phaedon cochleariae, Diabrotica spp., Psylliodes chrysocephala,    Epilachna varivestis, Atomaria spp., Oryzaephilus surinamensis,    Anthonomus spp., Sitophilus spp., Otiorrhynchus sulcatus,    Cosmopolites sordidus, Ceuthorrhynchus assimilis, Hypera postica,    Dermestes spp., Trogoderma spp., Anthrenus spp., Attagenus spp.,    Lyctus spp., Meligethes aeneus, Ptinus spp., Niptus hololeucus,    Gibbium psylloides, Tribolium spp., Tenebrio molitor, Agriotes spp.,    Conoderus spp., Melolontha melolontha, Amphimallon solstitialis and    Costelytra zealandica;-   (17) from the order Hymenoptera, for example Diprion spp.,    Hoplocampa spp., Lasius spp., Monomorium pharaonis and Vespa spp.;-   (18) from the order Diptera, for example Aedes spp., Anopheles spp.,    Culex spp., Drosophila melanogaster, Musca spp., Fannia spp.,    Calliphora erythrocephala, Lucilia spp., Chrysomyia spp., Cuterebra    spp., Gastrophilus spp., Hyppobosca spp., Stomoxys spp., Oestrus    spp., Hypoderma spp., Tabanus spp., Tannia spp., Bibio hortulanus,    Oscinella frit, Phorbia spp., Pegomyia hyoscyami, Ceratitis    capitata, Dacus oleae, Tipula paludosa, Hylemyia spp. and Liriomyza    spp.;-   (19) from the order Siphonaptera, for example Xenopsylla cheopis and    Ceratophyllus spp.;-   (20) from the class of arachnids, for example Scorpio maurus,    Latrodectus mactans, Acarus siro, Argas spp., Ornithodoros spp.,    Dermanyssus gallinae, Eriophyes ribis, Phyllocoptruta oleivora,    Boophilus spp., Rhipicephalus spp., Amblyomma spp., Hyalomma spp.,    Ixodes spp., Psoroptes spp., Chorioptes spp., Sarcoptes spp.,    Tarsonemus spp., Bryobia praetiosa, Panonychus spp., Tetranychus    spp., Hemitarsonemus spp. and Brevipalpus spp.; and-   (21) the plant-parasitic nematodes, for example, Pratylenchus spp.,    Radopholus similis, Ditylenchus dipsaci, Tylenchulus semipenetrans,    Heterodera spp., Globodera spp., Meloidogyne spp., Aphelenchoides    spp., Longidorus spp., Xiphinema spp., Trichodorus spp. and    Bursaphelenchus spp.

The active compounds according to the invention, in combination withgood plant tolerance and favourable toxicity to warm-blooded animals andbeing tolerated well by the environment, are suitable for protectingplants and plant organs, for increasing the harvest yields, forimproving the quality of the harvested material and for controllinganimal pests, in particular insects, arachnids, helminths, nematodes andmolluscs, which are encountered in agriculture, in horticulture, inanimal husbandry, in forests, in gardens and leisure facilities, in theprotection of stored products and of materials, and in the hygienesector. They may be preferably employed as plant protection agents. Theyare active against normally sensitive and resistant species and againstall or some stages of development. The abovementioned pests include:

From the order of the Anoplura (Phthiraptera), for example, Damaliniaspp., Haematopinus spp., Linognathus spp., Pediculus spp., Trichodectesspp.

From the class of the Arachnida, for example, Acarus siro, Aceriasheldoni, Aculops spp., Aculus spp., Amblyomma spp., Argas spp.,Boophilus spp., Brevipalpus spp., Bryobia praetiosa, Chorioptes spp.,Dermanyssus gallinae, Eotetranychus spp., Epitrimerus pyri,Eutetranychus spp., Eriophyes spp., Hemitarsonemus spp., Hyalomma spp.,Ixodes spp., Latrodectus mactans, Metatetranychus spp., Oligonychusspp., Ornithodoros spp., Panonychus spp., Phyllocoptruta oleivora,Polyphagotarsonemus latus, Psoroptes spp., Rhipicephalus spp.,Rhizoglyphus spp., Sarcoptes spp., Scorpio maurus, Stenotarsonemus spp.,Tarsonemus spp., Tetranychus spp., Vasates lycopersici.

From the class of the Bivalva, for example, Dreissena spp.

From the order of the Chilopoda, for example, Geophilus spp., Scutigeraspp.

From the order of the Coleoptera, for example, Acanthoscelides obtectus,Adoretus spp., Agelastica alni, Agriotes spp., Amphimallon solstitialis,Anobium punctatum, Anoplophora spp., Anthonomus spp., Anthrenus spp.,Apogonia spp., Atomaria spp., Attagenus spp., Bruchidius obtectus,Bruchus spp., Ceuthorhynchus spp., Cleonus mendicus, Conoderus spp.,Cosmopolites spp., Costelytra zealandica, Curculio spp., Cryptorhynchuslapathi, Dermestes spp., Diabrotica spp., Epilachna spp., Faustinuscubae, Gibbium psylloides, Heteronychus arator, Hylamorpha elegans,Hylotrupes bajulus, Hypera postica, Hypothenemus spp., Lachnosternaconsanguinea, Leptinotarsa decemlineata, Lissorhoptrus oryzophilus,Lixus spp., Lyctus spp., Meligethes aeneus, Melolontha melolontha,Migdolus spp., Monochamus spp., Naupactus xanthographus, Niptushololeucus, Oryctes rhinoceros, Oryzaephilus surinamensis, Otiorrhynchussulcatus, Oxycetonia jucunda, Phaedon cochleariae, Phyllophaga spp.,Popillia japonica, Premnotrypes spp., Psylliodes chrysocephala, Ptinusspp., Rhizobius ventralis, Rhizopertha dominica, Sitophilus spp.,Sphenophorus spp., Sternechus spp., Symphyletes spp., Tenebrio molitor,Tribolium spp., Trogoderma spp., Tychius spp., Xylotrechus spp., Zabrusspp.

From the order of the Collembola, for example, Onychiurus armatus.

From the order of the Dermaptera, for example, Forficula auricularia.

From the order of the Diplopoda, for example, Blaniulus guttulatus.

From the order of the Diptera, for example, Aedes spp., Anopheles spp.,Bibio hortulanus, Calliphora erythrocephala, Ceratitis capitata,Chrysomyia spp., Cochliomyia spp., Cordylobia anthropophaga, Culex spp.,Cuterebra spp., Dacus oleae, Dermatobia hominis, Drosophila spp., Fanniaspp., Gastrophilus spp., Hylemyia spp., Hyppobosca spp., Hypoderma spp.,Liriomyza spp., Lucilia spp., Musca spp., Nezara spp., Oestrus spp.,Oscinella frit, Pegomyia hyoscyami, Phorbia spp., Stomoxys spp., Tabanusspp., Tannia spp., Tipula paludosa, Wohifahrtia spp.

From the class of the Gastropoda, for example, Arion spp., Biomphalariaspp., Bulinus spp., Deroceras spp., Galba spp., Lymnaea spp.,Oncomelania spp., Succinea spp.

From the class of the helminths, for example, Ancylostoma duodenale,Ancylostoma ceylanicum, Acylostoma braziliensis, Ancylostoma spp.,Ascaris lubricoides, Ascaris spp., Brugia malayi, Brugia timori,Bunostomum spp., Chabertia spp., Clonorchis spp., Cooperia spp.,Dicrocoelium spp, Dictyocaulus filaria, Diphyllobothrium latum,Dracunculus medinensis, Echinococcus granulosus, Echinococcusmultilocularis, Enterobius vermicularis, Faciola spp., Haemonchus spp.,Heterakis spp., Hymenolepis nana, Hyostrongulus spp., Loa Loa,Nematodirus spp., Oesophagostomum spp., Opisthorchis spp., Onchocercavolvulus, Ostertagia spp., Paragonimus spp., Schistosomen spp.,Strongyloides fuelleborni, Strongyloides stercoralis, Stronyloides spp.,Taenia saginata, Taenia solium, Trichinella spiralis, Trichinellanativa, Trichinella britovi, Trichinella nelsoni, Trichinellapseudopsiralis, Trichostrongulus spp., Trichuris trichuria, Wuchereriabancrofti.

It is furthermore possible to control protozoa, such as Eimeria.

From the order of the Heteroptera, for example, Anasa tristis,Antestiopsis spp., Blissus spp., Calocoris spp., Campylomma livida,Cavelerius spp., Cimex spp., Creontiades dilutus, Dasynus piperis,Dichelops furcatus, Diconocoris hewetti, Dysdercus spp., Euschistusspp., Eurygaster spp., Heliopeltis spp., Horcias nobilellus, Leptocorisaspp., Leptoglossus phyllopus, Lygus spp., Macropes excavatus, Miridae,Nezara spp., Oebalus spp., Pentomidae, Piesma quadrata, Piezodorus spp.,Psallus seriatus, Pseudacysta persea, Rhodnius spp., Sahlbergellasingularis, Scotinophora spp., Stephanitis nashi, Tibraca spp., Triatomaspp.

From the order of the Homoptera, for example, Acyrthosipon spp.,Aeneolamia spp., Agonoscena spp., Aleurodes spp., Aleurolobusbarodensis, Aleurothrixus spp., Amrasca spp., Anuraphis cardui,Aonidiella spp., Aphanostigma piri, Aphis spp., Arboridia apicalis,Aspidiella spp., Aspidiotus spp., Atanus spp., Aulacorthum solani,Bemisia spp., Brachycaudus helichrysii, Brachycolus spp., Brevicorynebrassicae, Calligypona marginata, Carneocephala fulgida, Ceratovacunalanigera, Cercopidae, Ceroplastes spp., Chaetosiphon fragaefolii,Chionaspis tegalensis, Chlorita onukii, Chromaphis juglandicola,Chrysomphalus ficus, Cicadulina mbila, Coccomytilus halli, Coccus spp.,Cryptomyzus ribis, Dalbulus spp., Dialeurodes spp., Diaphorina spp.,Diaspis spp., Doralis spp., Drosicha spp., Dysaphis spp., Dysmicoccusspp., Empoasca spp., Eriosoma spp., Erythroneura spp., Euscelisbilobatus, Geococcus coffeae, Homalodisca coagulata, Hyalopterusarundinis, Icerya spp., Idiocerus spp., Idioscopus spp., Laodelphaxstriatellus, Lecanium spp., Lepidosaphes spp., Lipaphis erysimi,Macrosiphum spp., Mahanarva fimbriolata, Melanaphis sacchari,Metcalfiella spp., Metopolophium dirhodum, Monellia costalis,Monelliopsis pecanis, Myzus spp., Nasonovia ribisnigri, Nephotettixspp., Nilaparvata lugens, Oncometopia spp., Orthezia praelonga,Parabemisia myricae, Paratrioza spp., Parlatoria spp., Pemphigus spp.,Peregrinus maidis, Phenacoccus spp., Phloeomyzus passerinii, Phorodonhumuli, Phylloxera spp., Pinnaspis aspidistrae, Planococcus spp.,Protopulvinaria pyriformis, Pseudaulacaspis pentagona, Pseudococcusspp., Psylla spp., Pteromalus spp., Pyrilla spp., Quadraspidiotus spp.,Quesada gigas, Rastrococcus spp., Rhopalosiphum spp., Saissetia spp.,Scaphoides titanus, Schizaphis graminum, Selenaspidus articulatus,Sogata spp., Sogatella furcifera, Sogatodes spp., Stictocephala festina,Tenalaphara malayensis, Tinocallis caryaefoliae, Tomaspis spp.,Toxoptera spp., Trialeurodes vaporariorum, Trioza spp., Typhlocyba spp.,Unaspis spp., Viteus vitifolii.

From the order of the Hymenoptera, for example, Diprion spp., Hoplocampaspp., Lasius spp., Monomorium pharaonis, Vespa spp.

From the order of the Isopoda, for example, Armadillidium vulgare,Oniscus asellus, Porcellio scaber.

From the order of the Isoptera, for example, Reticulitermes spp.,Odontotermes spp.

From the order of the Lepidoptera, for example, Acronicta major, Aedialeucomelas, Agrotis spp., Alabama argillacea, Anticarsia spp., Barathrabrassicae, Bucculatrix thurberiella, Bupalus piniarius, Cacoecia podana,Capua reticulana, Carpocapsa pomonella, Chematobia brumata, Chilo spp.,Choristoneura fumiferana, Clysia ambiguella, Cnaphalocerus spp., Eariasinsulana, Ephestia kuehniella, Euproctis chrysorrhoea, Euxoa spp.,Feltia spp., Galleria mellonella, Helicoverpa spp., Heliothis spp.,Hofmannophila pseudospretelia, Homona magnanima, Hyponomeuta padella,Laphygma spp., Lithocolletis blancardella, Lithophane antennata,Loxagrotis albicosta, Lymantria spp., Malacosoma neustria, Mamestrabrassicae, Mocis repanda, Mythimna separata, Oria spp., Oulema oryzae,Panolis flammea, Pectinophora gossypiella, Phyllocnistis citrella,Pieris spp., Plutella xylostella, Prodenia spp., Pseudaletia spp.,Pseudoplusia includens, Pyrausta nubilalis, Spodoptera spp., Thermesiagemmatalis, Tinea pellionella, Tineola bisselliella, Tortrix viridana,Trichoplusia spp.

From the order of the Orthoptera, for example, Acheta domesticus, Blattaorientalis, Blattella germanica, Gryllotalpa spp., Leucophaea maderae,Locusta spp., Melanoplus spp., Periplaneta americana, Schistocercagregaria.

From the order of the Siphonaptera, for example, Ceratophyllus spp.,Xenopsylla cheopis.

From the order of the Symphyla, for example, Scutigerella immaculata.

From the order of the Thysanoptera, for example, Baliothrips biformis,Enneothrips flavens, Frankliniella spp., Heliothrips spp., Hercinothripsfemoralis, Kakothrips spp., Rhipiphorothrips cruentatus, Scirtothripsspp., Taeniothrips cardamoni, Thrips spp.

From the order of the Thysanura, for example, Lepisma saccharina.

The phytoparasitic nematodes include, for example, Anguina spp.,Aphelenchoides spp., Belonoaimus spp., Bursaphelenchus spp., Ditylenchusdipsaci, Globodera spp., Heliocotylenchus spp., Heterodera spp.,Longidorus spp., Meloidogyne spp., Pratylenchus spp., Radopholussimilis, Rotylenchus spp., Trichodorus spp., Tylenchorhynchus spp.,Tylenchulus spp., Tylenchulus semipenetrans, Xiphinema spp.

If appropriate, the compounds according to the invention can, at certainconcentrations or application rates, also be used as herbicides,safeners, growth regulators or agents to improve plant properties, or asmicrobicides, for example as fungicides, antimycotics, bactericides,viricides (including agents against viroids) or as agents against MLO(mycoplasma-like organisms) and RLO (rickettsia-like organisms). Ifappropriate, they can also be employed as intermediates or precursorsfor the synthesis of other active compounds.

In another embodiment this aspect of the invention, the compounds andcompositions of the invention are suitable for controlling pests such asinsects selected from the group consisting of Blatella germanica,Heliothis virescens, Leptinotarsa decemlineata, Tetramorium caespitumand combinations thereof.

In each aspect of the invention, the compounds and compositions of theinvention can be applied against a single pest or combinations thereof.

The composition containing the 1-aryl-5-alkyl pyrazole of the inventionmay be administered continuously, for treatment or prophylaxis, by knownmethods. Generally, a dose of from about 0.001 to about 50 mg per kg ofbody weight given as a single dose or in divided doses for a period offrom 1 to 5 days will be satisfactory but, of course, there can beinstances where higher or lower dosage ranges are indicated, and suchare within the scope of this invention. It is well within the routineskill of the practitioner to determine a particular dosing regimen for aspecific host and parasite.

In one treatment embodiment, the treatment is carried out so as toadminister to the animal, on a single occasion, a dose containingbetween about 0.001 and about 100 mg/kg of a 1-aryl-5-alkyl pyrazolecompound or between about 0.1 and about 200 μg/kg or about 100 μg/kg ofcompound. In another treatment embodiment, the treatment is via a directtopical administration such as a paste, pour-on, ready-to-use, spot-on,etc. type formulation. Higher amounts may be provided for very prolongedrelease in or on the body of the animal. In another treatmentembodiment, the amount of 1-aryl-5-alkyl pyrazole compound for birds andanimals which are small in size is greater than about 0.01 mg, and inanother embodiment for the treatment of small sized birds and animals,the amount of 1-aryl-5-alkyl pyrazole compound is between about 1 andabout 100 mg/kg of weight of animal.

The solutions according to the invention may be applied using any meansknown per se, e.g. using an applicator gun or a metering flask.

This method serves to cleanse the skin and the hairs of the animals byeliminating the parasites which are present thereon, as well as theirresidues and dejections. The result of this is that the animals are nolonger stressed by the parasites and their bites, this having positiveconsequences, for example on their growth and on the use of their foodration.

In one embodiment, a direct pour-on skin formulation according to thepresent invention can provide long-lasting and broad-spectrum efficacywhen the solution is applied to the animal's back, e.g. along the lineof the back at one or more points.

According to a first embodiment for administering direct pour-onformulations, the process comprises applying the solution to theanimals, the application being repeated every month or every two months.

According to a second embodiment for administering direct pour-onformulation, the process comprises applying the solution to livestockanimals before they arrive in the Feed Lot, it being possible for thisapplication to be the final one before the animals are slaughtered.

Obviously, the process may also consist in combining these twoembodiments, namely the first followed by the second.

In another embodiment, the compounds of the invention are administeredin spot-on formulations. While not wishing to be bound by theory, it isbelieved that these formulations work by dissolution of the dose in thenatural oils of the host's skin, fur or feathers. From there, the activeagent(s) distribute around the host's body through the sebaceous glandsof the skin. The therapeutic agent also remains in the sebaceous glands.Thus, the glands provide a natural reservoir for the active agent thatallows for the agent to be drained back out to the follicles to reapplyitself to the skin and hair. This, in turn, provides for longer timeperiods between application as well as eliminating the need tore-administer the dose after the host becomes wet because of rain,bathes, etc. The inventive formulation has the further advantage of notbeing directly deposited on the skin or fur, where self-grooming animalscould orally ingest the therapeutic agent, thereby becoming sick orpossibly interacting with other therapeutic agent being orallyadministered.

In one embodiment of the location of administration, a singleformulation containing the active agent in a substantially liquidcarrier and in a form which makes possible a single application, or anapplication repeated a small number of times, will be administered tothe animal over a localized region of the animal, e.g. between the twoshoulders. In one embodiment of the invention, the localized region hasa surface area of about 10 cm² or larger. In another embodiment of theinvention, the localized region has a surface are of between about 5 andabout 10 cm² area.

The invention is further described by the following non-limitingexamples which further illustrate the invention, and are not intended,nor should they be interpreted to, limit the scope of the invention.

EXAMPLES Preparation Examples

All temperatures are given in degrees Centigrade; room temperature means20 to 25° C. Reagents were purchased from commercial sources or preparedfollowing literature procedures.

Unless otherwise noted, purification by reverse phase columnchromatography was performed by dissolving the crude residue in a smallvolume of DMSO and filtering through a 0.45 micron (nylon disc) syringefilter. The solution was then purified on an HPLC purification systemmanaged by the Chromeleon™ software using a 50 mm Varian Dynamax HPLC21.4 mm Microsorb Guard-8 C8 column. The initial MeOH:H₂O solventmixture was selected as appropriate for the target compound. Thisinitial mixture was maintained for 0.5 minutes then changed by a lineargradient to a final concentration of 100% MeOH over 5 minutes. 100% MeOHwas maintained for 2 more minutes. Total run time was 8 minutes. Theresulting fractions were analyzed, combined as appropriate, and thenevaporated to provide purified material.

Proton and fluorine magnetic resonance (respectively 1H NMR and 19F NMR)spectra were recorded on a Varian INOVA NMR spectrometer [400 MHz (1H)and 377 MHz (19F)]. All spectra were determined in the solventsindicated. Chemical shifts are reported in ppm downfield oftetramethylsilane (TMS), referenced to the residual proton peak of therespective solvent peak for 1H NMR. Interproton coupling contants arereported in Hertz (Hz). LC-MS spectra were obtained using aThermofinnigan AQA MS ESI instrument, using a Phenomenex Aqua 5 micronC18 125A 50×4.60 mm column and a linear gradient from 55% MeOH: 1% CH3CNin H2O to 100% MeOH over 3 minutes. 100% MeOH was maintained for 2minutes. Melting points were determined using a Thomas Hoover capillarymelting point apparatus and are uncorrected.

Example 13-Cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methyl-4-trifluoromethylthiopyrazole(Compound No 1)

A solution of L-selectride (14.2 mL, 1 M in THF) was added to a solutionof5-bromomethyl-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole(6.75 g) in THF at −78° C. The reaction mixture was allowed to warm toroom temperature with stirring over one hour, and then hydrogen peroxide(2.6 mL, 30% w/v) was added followed by water and ethyl acetate. Theorganic layer was separated, dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure. The crude product waspurified by chromatography (SiO₂, heptane/EA) to afford the titlecompound as a white solid (3.67 g, 65%). MS (ES): M/Z [M+NH₄]=437. 1HNMR: (400 MHz, DMSO-d₆): 2.30 (s, 3H) and 8.39 (s, 2H). 19F NMR (376MHz, DMSO-d₆): −44.03 (s, 3F) and −61.98 (s, 3F).

The starting material,5-bromomethyl-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole,was prepared as follows:

-   -   a. A solution of        5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole        (87.5 g), prepared as described in EP-A-0 295 117, was added        dropwise to a suspension of tert-butylnitrite (32 mL), methyl        acrylate (149 mL) and copper bromide (55.6 g) in acetonitrile.        The reaction mixture was stirred overnight. The resulting        mixture was diluted with diethylether and washed with water. The        organic layer was dried over anhydrous magnesium sulfate,        filtered and concentrated under reduced pressure. Trituration of        the residue from ethyl acetate and heptane gave        5-(2′-bromo-2′-carbomethoxy)ethyl-3-cyano-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-trifluoromethylthiopyrazole        as a tanned solid (73.7 g, 78%).    -   b. 1,8-diazabicyclo-[5.4.0]-undec-7-ene (4.4 mL) was added to a        solution of        5-(2′-bromo-2′-carbomethoxy)ethyl-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole        (15.1 g) dissolved in toluene. After stirring for 40 minutes,        the mixture was diluted with ethyl acetate, washed with water,        10% aqueous hydrochloric acid solution and water. The organic        phase was dried over anhydrous magnesium sulfate, filtered and        concentrated under reduced pressure to give        3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-(E-2-methoxycarbonylethenyl)-4-trifluoromethylthiopyrazole        as a white solid (11.0 g 85%).    -   c. Ozone was bubbled through a solution of the        3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-(E-2-methoxycarbonyl-ethenyl)-4-trifluoromethylthiopyrazole        (4.8 g) in dichloromethane and methanol for 3 h at −78° C. After        3 hours the intensely blue solution was decolorized with oxygen        gas, and then treated with dimethylsulfide at −78° C. This        reaction mixture was allowed to warm to room temperature        whereupon the mixture was washed with a 10% aqueous solution of        sodium bisulfate. The resulting mixture was extracted with ethyl        acetate. The organic layer was dried over anhydrous magnesium        sulfate, filtered and concentrated under reduced pressure to        give        3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-formyl-4-trifluoromethylthiopyrazole        as a white solid (4.2 g).    -   d.        3-Cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-formyl-4-trifluoromethylthiopyrazole        (4.2 g) was dissolved in absolute ethanol and sodium borohydride        (0.61 g) added portion wise at 0° C. This reaction mixture was        stirred and allowed to warm to room temperature over 2 h        whereupon water was added. The resulting mixture was extracted        with ethyl acetate. The organic layer was dried over anhydrous        magnesium sulfate, filtered and concentrated under reduced        pressure to give a residue that was purified by chromatography        (SiO₂, heptane/EA) to afford        3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-hydroxymethyl-4-trifluoromethylthiopyrazole        as a white solid (4.03 g, 94%).    -   e. Bromine (2.8 mL) was slowly added to a solution of        triphenylphosphine (12 g) in dichloromethane. After stirring for        30 minutes, it was transferred via syringe to a solution of        3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-hydroxymethyl-4-trifluoromethylthiopyrazole        (9 g) in dichloromethane. After stirring for 2 hours, solvent        was evaporated under reduced pressure. The residue was purified        by chromatography (SiO₂, heptane/EA) to afford        5-bromomethyl-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole        as a pale yellow solid (9.9 g, 96%).

Example 21-(2-Chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-5-methyl-4-trifluoromethylthiopyrazole(Compound No 7)

Using a procedure similar to that described in Example 1, exceptstarting from5-amino-3-cyano-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-4-trifluoro-methylthiopyrazole,the title compound was isolated as a white solid. 1H NMR: (400 MHz,DMSO-d₆): 2.34 (s, 3H) and 8.27 (m, 2H). 19F NMR (376 MHz, DMSO-d₆):−43.96 (s, 3F), −62.08 (s, 3F) and −115.04 (s, 1F).

The5-amino-3-cyano-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazolewas prepared as follows:

-   -   a. N-Chlorosuccinimide (4.1 g) was added to a solution of        2-fluoro-4-trifluoromethylaniline in acetonitrile under nitrogen        and the mixture heated to 75° C. over night. The mixture was        concentrated, diluted with ether, washed with water, saturated        sodium bicarbonate solution and brine. The organic layers were        dried over anhydrous magnesium sulfate, filtered and        concentrated under reduced pressure to give        2-chloro-6-fluoro-4-trifluoromethylaniline as a liquid (5.9 g).        Rf=0.6 (2:8 EA/heptane); 1H NMR: (400 MHz, CDCl₃) 4.41 (bs, 2H);        7.20 (dd, 1H, J=10.5, 1.5 Hz) and 7.36 (s, 1H). 19F NMR (376        MHz, CDCl₃): −130.78 (s, 1F) and −61.98 (s, 3F).    -   b. A solution of 2-chloro-6-fluoro-4-trifluoromethylaniline        (5 g) in acetic acid was added dropwise to a suspension of        nitrosyl sulphuric acid (11.2 g) in acetic acid at 15° C. After        stirring for 1 hour, this reaction mixture was added dropwise to        a suspension of 1,2-dicyano-3-hydroxyprop-2-ene potassium salt        (10 g) and sodium acetate trihydrate (32 g) in a mixture of        sodium acetic and water at 7° C. After stirring for 1 hour, this        reaction mixture was diluted with water and extracted with        dichloromethane. The organic layers were stirred vigorously with        a 30% ammonium hydroxide solution for 10 minutes, separated,        dried over anhydrous magnesium sulfate, filtered and        concentrated under reduced pressure to give a residue that was        purified by chromatography (SiO₂, heptane/EA) to afford        5-amino-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyanopyrazole        as a yellow-orange solid (5.1 g, 71%). R_(f)=0.25 (3:7        EA/heptane); 1H NMR (400 MHz, DMSO-d₆): 5.94 (s, 1H), 6.14 (s,        2H) and 8.06-8.10 (m, 2H). 19F NMR (376, DMSO-d₆): −61.98 (s,        3F) and −114.38 (s, 1F).

The 1,2-dicyano-3-hydroxyprop-2-ene potassium salt was prepared asfollows:

A solution of potassium tert-butoxide (29 g) in tert-butanol was addeddropwise to a solution of succinonitrile (20 g) and ethyl formate (22.7g) in a 5:1 mixture of toluene and tert-butanol at 5° C. After stirringfor 6 hours, the solid was filtered off, washed once with ethanol andthree times with methyl tert-butyl ether and then dried over night in avacuum oven at 55° C. to give 1,2-dicyano-3-hydroxyprop-2-ene potassiumsalt as a tan solid (35 g, 96%).

-   -   c. A solution of        5-amino-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyanopyrazole        (3 g) in dichloromethane was stirred at 0° C. and treated        dropwise with a solution of trifluoromethylsulphenyl chloride        (2 g) in dichloromethane during 1 hour. After stirring overnight        at room temperature, nitrogen was bubbled trough the solution        for 5 minutes. Then the mixture was washed with water, saturated        sodium bicarbonate solution and brine. The organic layers were        dried over anhydrous magnesium sulfate, filtered and        concentrated under reduced pressure to give a residue that was        purified by chromatography (SiO₂, heptane/EA) to afford        5-amino-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthiopyrazole        as a white solid (3.5 g, 86%). R_(f)=0.4 (3:7 EA/heptane); 1H        NMR (400 MHz, DMSO-d₆) 7.21 (bs, 2H) and 8.10-8.14 (m, 2H). 19F        NMR (376 MHz, DMSO-d₆): −45.33 (s, 3F), −62.08 (s, 3F) and        −114.62 (s, 1F).

Example 33-Cyano-1-(2-fluoro-4-trifluoromethylphenyl)-5-methyl-4-trifluoromethylthiopyrazole(Compound No 13)

Using a procedure similar to that described in Example 1, exceptstarting from5-amino-3-cyano-1-(2-fluoro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole,the title compound was isolated as a white solid. 1H NMR: (400 MHz,DMSO-d₆): 2.38 (s, 3H), 7.89 (d, 1H), 8.05 (t, 1H) and 8.16-8.19 (m,1H). 19F NMR (376 MHz, DMSO-d₆): −43.68 (s, 3F), −61.86 (s, 3F) and−119.69 (m, 1F).

The starting material,5-amino-3-cyano-1-(2-fluoro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole,was prepared from 2-fluoro-4-trifluoromethylaniline following a similarprocedure to that described in Example 2, steps b,c.

Example 4A1-(2-Chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-4-dichlorofluoromethylthio-5-methylpyrazole(Compound No 26)

Using a procedure similar to that described in Example 1, exceptstarting from5-amino-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-4-dichlorofluoromethylthiopyrazole,the title compound was isolated as a white solid. MS (ES): M/Z[M+H+CH₃OH]=468. 1H NMR: (400 MHz, CDCl₃): 2.34 (s, 3H), 7.57 (dd,J=8.3, 1.4 Hz 1H) and 7.74 (bs, 1H). 19F NMR (376 MHz, CDCl₃): −21.10(s, 1F), −63.78 (s, 3F) and −113.47 (d, J=8.3 Hz, 1F).

The starting material,5-amino-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-4-dichlorofluoromethylthiopyrazole,was prepared by the following procedure:

-   -   a. Sulfur monochloride (0.78 g) was added at 10° C. to a        dichloromethane solution of        5-amino-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyanopyrazole        (3.54 g), described in Example 2 step b. After stirring        overnight at room temperature, nitrogen was bubbled trough the        solution for 5 minutes. The solid precipitate was filtered,        washed with dichloromethane, heptane and dried under reduced        pressure to give        5-amino-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyanopyrazol-4-yl        disulfide as a pale yellow solid (2.8 g, 72%). R_(f)=0.3 (4:6        EA/heptane)    -   b. Sodium dithionite (6.2 g), disodium hydrogen phosphate        (4.3 g) and fluorotrichloromethane (5.2 g) were added with        stirring to a solution of        5-amino-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyanopyrazol-4-yl        disulfide (5.15 g) in a 2:1 mixture of N,N-dimethylformamide and        water at 15° C. After stirring for one hour, the mixture was        poured into ice and stirred for 30 minutes. The solid was        filtered off, washed with water and dried to give        5-amino-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-4-dichlorofluoromethylthiopyrazole        as a white solid (4.1 g, 64%). R_(f)=0.4 (3:7 EA/heptane).

Example 4B1-(2-Chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-4-dichlorofluoromethylthio-5-methylpyrazole(Compound No 26—alternative method)

-   a. Sodium hydroxide (1.65 M, 250 mL)) was added to a solution of    1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-ethoxycarbonyl-5-methyl-4-fluorodichloromethylthiopyrazole    (66.0 g) in ethanol (750 mL) and THF (100 mL). After stirring 60    minutes, a six normal aqueous hydrochloric acid solution (70 mL) was    slowly added. The mixture was concentrated and the residue dissolved    up into 500 mL ethyl acetate and washed with saturated sodium    bicarbonate solution, water and then brine. The organic phase was    dried over anhydrous sodium sulfate, filtered and concentrated under    reduced pressure to give a light yellow solid residue that was used    in the next step without further purification. MS (ES): M/Z    [M+H]=455. 1H NMR (400 MHz, CDCl₃): 7.79 (s, 2H), 6.66 (s, 1H) and    2.18 (s, 3H). 19F NMR (376 MHz, CDCl₃): −20.35 (s, 1F), −63.74 (s,    3F) and −113.34 (d, J=7.9 Hz, 1F).-   b. Oxalyl chloride (35 mL) was added dropwise to a mixture of the    above residue in dichloromethane (350 mL) cooled in an ice bath.    Three drops of N,N-dimethylformamide was added and the mixture    removed from the ice bath. After two hours stirring, solvent was    evaporated under reduced pressure to give a solid residue that was    dissolved in dichloromethane and cooled to 0° C. Dry ammonia gas was    bubbled through the reaction mixture for 5 minutes before allowing    the reaction mixture to warm to room temperature. After stirring for    one hour, the mixture was concentrated to a crude solid which was    washed with water and dried to give an off white solid residue that    was used in the next step without further purification. R_(f)=0.25    (3:7 EA/heptane). 1H NMR (400 MHz, CDCl₃): 7.72 (s, 1H), 7.54 (d,    J=8.0 Hz, 1H) and 2.36 (s, 3H). 19F NMR (376 MHz, CDCl₃): −20.35 (s,    1F), −63.74 (s, 3F) and −113.32 (d, J=7.9 Hz, 1F).-   c. Oxalyl chloride (42 mL) was added dropwise to a stirred solution    of N,N-dimethylformamide (36 mL) in acetonitrile (500 mL) at 0° C.    After stirring for 10 minutes, a solution of the above residue in    acetonitrile (400 mL) and N,N-dimethylformamide (20 mL) was added    dropwise and the reaction mixture was stirred 1 h. allowing it to    warm to room temperature. The reaction mixture was poured rapidly    into stirring ice water and the resulting solid filtered, washed    with water and dried to give the title compound as a white solid    (57.0 g, 96%). R_(f)=0.75 (3:7 EA/heptane). MS (ES): M/Z [M+H]=436.    Elemental analysis: Calculated: C, 35.76, H, 1.15; N, 9.62, S, 7.34,    Cl, 24.36 and F, 21.76; Found: C, 35.88, H, 1.15; N, 9.53, S, 7.39,    Cl, 24.29 and F, 21.80. 1H NMR (500 MHz, CD₂Cl₂): 7.77 (s, 1H), 7.60    (d, J=8.3 Hz, 1H) and 2.34 (s, 3H). 19F NMR (470 MHz, CD₂Cl₂):    −21.43 (s, 1F), −64.17 (s, 3F) and −114.35 (d, J=8.4 Hz, 1F). ¹³C    NMR (126 MHz, CD₂Cl₂): 159.04 (d, J=259.9 Hz, 1C), 151.10 (s, 1C),    135.90 (s, 1C), 135.51 (qd, J=34.9, 8.8 Hz, 1C), 134.21 (s, 1C),    128.00 (d, J=15.2 Hz, 1C), 124.18 (q, J=3.3 Hz, 1C), 122.60 (qd,    J=273.5, 3.0 Hz, 1C), 121.58 (d, J=334.1 Hz, 1C), 114.09 (dq,    J=23.0, 3.6 Hz, 1C), 112.14 (s, 1C), 110.75 (s, 1C), 10.81 (s, 1C),

The starting material,1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-ethoxycarbonyl-4-dichlorofluoromethylthio-5-methylpyrazole,was prepared as follows:

A 1.1 normal ethanolic solution of hydrochloric acid (115 mL) was addedto a solution of 2-chloro-6-fluoro-4-trifluoromethylphenylhydrazine (24g) in 200 mL ethanol cooled in an ice bath. Ethyl3-dichlorofluoromethylthio-2,4-dioxovalerate (38.4 g) was added and theresulting mixture stirred overnight allowing it to warm to roomtemperature. The mixture was concentrated by removing 150 mL ethanol,cooled to approximately 0° C. in an ice bath and the solid precipitatefiltered and washed with cold ethanol to afford1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-ethoxycarbonyl-5-methylpyrazoleas a white solid (34.5 g, 68%). R_(f)=0.65 (3:7 EA/heptane). MS (ES):M/Z [M+H]=483. 1H NMR (400 MHz, CDCl₃): 7.70 (s, 1H), 7.52 (dd, J=8.3,1.7 Hz, 1H), 4.47 (m, 2H), 2.33 (s, 3H) and 1.42 (t, J=7.1 Hz, 3H). 19FNMR (376 MHz, CDCl₃): −20.36 (s, 1F), −63.74 (s, 3F) and 113.24 (d,J=8.6 Hz, 1F).

Ethyl 3-dichlorofluoromethylthio-2,4-dioxovalerate used above wasprepared as follows:

Triethylamine (5.5 mL, 4.0 g) was added at 0° C. to a solution ofethyl-2,4-dioxovalerate (5 mL, 5.6 g) in 125 mL dichloromethane. Afterstirring for 10 minutes, a solution of dichlorofluoromethyl sulfenylchloride (4 mL, 6.8 g from Marshallton, King, N.C.-USA) in 30 mLdichloromethane was added dropwise at 0° C. After stirring 30 minutes atapproximately 0° C. the mixture was let stirred at room temperatureovernight and then was concentrated under reduce pressure, dissolved inethyl acetate, filtered and concentrated to give an oily residue thatwas purified by chromatography (SiO₂, heptane/EA) to afford ethyl3-dichlorofluoromethylthio-2,4-dioxovalerate as a pale yellow liquid(7.5 g, 81%). 1H NMR (400 MHz, CD₂Cl₂): 4.35 (q, J=7.2 Hz, 2H), 2.51 (s,3H) and 1.34 (t, J=7.1 Hz, 3H). 19F NMR (376 MHz, CD₂Cl₂): −21.67 (s,1F).

Another alternative procedure was used to prepare1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-ethoxycarbonyl-4-dichlorofluoromethylthio-5-methylpyrazole:

Potassium carbonate (100 mg) was added as a solid to a solution of4-dichlorofluoromethylthio-3-ethoxycarbonyl-5-methyl-1-H-pyrazole (100mg) and 3-chloro-4,5-difluorobenzotrifluoride (110) inN-methylpyrrolidinone (2 mL). The mixture in sealed tube was heated to100° C. for 10 min with a microwave synthesis system (CEM, Matthews,N.C.-USA) then cooled to room temperature and filtered over a pad ofcelite. The filtrate was concentrated under reduced pressure to give aresidue that was purified by chromatography (SiO₂, heptane/EA) to afford1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-ethoxycarbonyl-5-methyl-pyrazoleas a white solid (51 mg, 30%).

Preparation of4-dichlorofluoromethylthio-3-ethoxycarbonyl-5-methyl-1-H-pyrazole usedabove is described below.

A 1.1 normal ethanolic solution of hydrochloric acid (32 mL) was addedto a solution of hydrazine (1.25 g, 1.23 mL) in 100 mL ethanol cooled inan ice bath. Ethyl 3-dichlorofluoromethylthio-2,4-dioxovalerate (9.3 g)was added and the resulting mixture stirred overnight allowing it towarm to room temperature. The mixture was concentrated and the residuedissolved up into ethyl acetate, washed with saturated sodiumbicarbonate solution and then brine. The organic layer was dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to give a residue that was purified by chromatography (SiO₂,heptane/EA) to afford4-dichlorofluoromethylthio-3-ethoxycarbonyl-5-methyl-1-H-pyrazole as awhite solid (8.0 g, 87%). R_(f)=0.5 (1:1 EA/heptane). 1H NMR (400 MHz,CDCl₃): 12.64 (br s, 1H), 4.43 (q, 2H), 2.50 (s, 3H) and 1.39 (t, 3H,CH₃). 1H NMR (400 MHz, DMSO-d6): 13.92 (br s, 1H), 4.28 (q, 2H), 2.53(s, 3H) and 1.28 (t, 3H). 19F NMR (376 MHz, DMSO-d6): −153.31 (s, 1F).

Example 53-Cyano-4-dichlorofluoromethylthio-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methylpyrazole(Compound No 15)

Using a procedure similar to that described in Example 1, exceptstarting from5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-dichlorofluoromethylthiopyrazole,the title compound was isolated as a white solid. MS (ES): M/Z[M+H+CH₃OH]=485. 1H NMR: (400 MHz, DMSO-d₆): 2.31 (s, 3H) and 8.39 (s,2H). 19F NMR (376 MHz, DMSO-d₆): −20.88 (s, 1F) and −61.97 (s, 3F).

The starting material,5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-dichlorofluoromethylthiopyrazole,was prepared following a similar procedure to that described in Example4, steps a,b, from5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole thatitself, was prepared using a similar procedure to that described inExample 2, steps b,c from 2,6-dichloro-4-trifluoromethylyaniline.

Example 63-Cyano-1-(2,6-dichloro-4-trifluoromethoxyphenyl)-5-methyl-4-trifluoromethylthiopyrazole(Compound No 17)

Using a procedure similar to that described in Example 1, exceptstarting from5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethoxyphenyl)-4-trifluoromethylthiopyrazole,described in EP-A-0 295 117, the title compound was isolated as a whitesolid. MS (ES): M/Z [M+H]=436. 1H NMR: (400 MHz, DMSO-d₆): 2.29 (s, 3H)and 8.08 (s, 2H). 19F NMR (376 MHz, DMSO-d₆): −44.09 (s, 3F) and −57.41(s, 3F).

Example 73-Cyano-4-dichlorofluoromethylthio-1-(2,6-dichloro-4-trifluoromethoxyphenyl)-5-methylpyrazole(Compound No 23)

Using a procedure similar to that described in Example 1, exceptstarting from5-amino-3-cyano-4-dichlorofluoromethylthio-1-(2,6-dichloro-4-trifluoromethoxyphenyl)pyrazole,the title compound was isolated as a white solid. MS (ES): M/Z[M+NH₄]=485. 1H NMR: (400 MHz, CDCl₃): 2.30 (s, 3H) and 7.44 (s, 2H).19F NMR (376 MHz, CDCl₃): −20.99 (s, 1F) and −58.28 (s, 3F).

The starting material,5-amino-3-cyano-4-dichlorofluoromethylthio-1-(2,6-dichloro-4-trifluoromethoxyphenyl)pyrazole,was prepared following a similar procedure to that described in Example4, steps a,b, from5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethoxyphenyl)pyrazole thatitself, was prepared from 2,6-dichloro-4-trifluoromethoxyaniline using asimilar procedure to that described in Example 2, steps b,c.

Example 81-(2-Chloro-4-trifluoromethylphenyl)-3-cyano-4-dichlorofluoromethylthio-5-methylpyrazole(Compound No 27)

Using a procedure similar to that described in Example 1, exceptstarting from5-amino-1-(2-chloro-4-trifluoromethylphenyl)-3-cyano-4-dichlorofluoromethylthiopyrazole,the title compound was isolated as a white solid. 1H NMR: (400 MHz,CDCl₃): 2.35 (s, 3H), 7.63 (d, J=8.2 Hz, 1H), 7.78 (dd, J=8.2, 1.4 Hz,1H) and 7.91 (d, J=1.5 Hz, 1H). 19F NMR (376 MHz, CDCl₃): −21.10 (s,1F), −63.78 (s, 3F) and −113.47 (d, J=8.3 Hz, 1F).

The starting material,5-amino-1-(2-chloro-4-trifluoromethylphenyl)-3-cyano-4-dichlorofluoromethylthiopyrazole,was prepared following a similar procedure to that described in Example4, steps a,b from5-amino-1-(2-chloro-4-trifluoromethylphenyl)-3-cyanopyrazole that,itself, was prepared from 2-chloro-4-trifluoromethylaniline using asimilar procedure to that described in Example 2, steps b,c.

Example 93-Cyano-1-(2,6-dichloro-4-pentafluorothiophenyl)-5-methyl-4-trifluoromethylthiopyrazole(Compound No 34)

Using a procedure similar to that described in Example 1, exceptstarting from5-amino-3-cyano-1-(2,6-dichloro-4-pentafluorothiophenyl)-4-trifluoromethylthiopyrazole,the title compound was isolated as a white solid. 1H NMR: (400 MHz,CDCl₃): 2.31 (s, 3H) and 7.96 (s, 2H). 19F NMR (376 MHz, CDCl₃): −44.10(s, 3F), 62.68 (d, J=152 Hz, 4F) and 78.16-79.77 (quintet, J=154 Hz,1F).

5-amino-3-cyano-1-(2,6-dichloro-4-pentafluorothiophenyl)-4-trifluoromethylthiopyrazole,was prepared from 4-pentafluorothioaniline following a similar procedureto that described in Example 2, steps a,b,c, except that 2.2 equivalentsof N-chlorosuccinimide were used in step a.

Example 104-Chlorodifluoromethylthio-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-5-methylpyrazole(Compound No 36)

Using a procedure similar to that described in Example 1, exceptstarting from5-amino-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-4-chlorodifluoromethylthio-3-cyanopyrazole,the title compound was isolated as a white solid. MS (ES): M/Z[M+NH₄]437. 1H NMR: (400 MHz, CDCl₃): 2.33 (s, 3H), 7.56 (dd, J=8.3, 1.4Hz 1H) and 7.74 (bs, 1H). 19F NMR (376 MHz, CDCl₃): −63.79 (s, 3F),−113.48 (d, J=8.4 Hz, 1F) and −161.99 (s, 2F).

The starting material,5-amino-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-4-chlorodifluoromethylthio-3-cyanopyrazole,was prepared following the same procedure to that described in Example4, steps a,b, except that bromochlorodifluoromethane was used in step binstead of fluorotrichloromethane.

Example 113-Cyano-4-dichlorofluoromethylthio-1-(2,6-dichloro-4-pentafluorothiophenyl)-5-methylpyrazole(Compound No 42)

Using a procedure similar to that described in Example 1, exceptstarting from5-amino-3-cyano-4-dichlorofluoromethylthio-1-(2,6-dichloro-4-pentafluorothiophenyl)pyrazole,the title compound was isolated as a white solid. 1H NMR: (400 MHz,CDCl₃): 2.31 (s, 3H) and 7.96 (s, 2H). 19F NMR (376 MHz, CDCl₃): −21.03(s, 1F), 62.70 (d, J=152 Hz, 4F) and 78.19-79.81 (quintet, J=154 Hz,1F).

The starting material,5-amino-3-cyano-4-dichlorofluoromethylthio-1-(2,6-dichloro-4-pentafluorothiophenyl)pyrazole,was prepared following a similar procedure to that described in Example4, steps a,b from5-amino-3-cyano-1-(2,6-dichloro-4-pentafluorothiophenyl)pyrazole that,itself, was prepared using a similar procedure to that described inExample 2, steps a,b from 4-pentafluorothioaniline, except that 2.2equivalents of N-chlorosuccinimide were used in step a.

Example 123-cyano-1-(2,6-difluoro-4-trifluoromethylphenyl)-5-methyl-4-trifluoromethylthiopyrazole(Compound No 6)

Cesium fluoride (2.7 g) was added to a solution of3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methyl-4-trifluoromethylthiopyrazole(0.7 g) in N-methylpyrrolidinone. The reaction mixture was heated at 10°C. overnight. The reaction mixture was then cooled to room temperatureand water was added. The resulting mixture was extracted with ethylacetate. The organic layer was dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure to give a residue thatwas purified by chromatography (SiO₂, heptane/EA) to afford the titlecompound as a white solid (0.38 g, 59%). 1H NMR: (400 MHz, CDCl₃): 2.38(s, 3H) and 7.49 (d, J=8 Hz, 2H). 19F NMR (376 MHz, CDCl₃): −43.83 (s,3F), −63.91 (s, 3F) and −113.98 (d, J=7 Hz, 2F).

Preparation of3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methyl-4-trifluoromethylthiopyrazoleis described in Example 1.

Example 131-(2-chloro-6-methyl-4-trifluoromethylphenyl)-3-cyano-5-methyl-4-trifluoromethylthiopyrazole(Compound No 43)

A solution of trimethylboroxine (83 mg),tris(dibenzylideneacetone)dipalladium (10 mg), Xantphos (18 mg),potassium carbonate (165 mg) and3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methyl-4-trifluoromethylthiopyrazole(250 mg) in dioxane was heated in a microwave for 20 minutes at 130° C.in a 10 ml sealed Pyrex glass tube. The reaction mixture was cooled toroom temperature then diluted with ethyl acetate and filtered overCelite. The organic filtrate was washed with water, dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure togive a residue that was purified by chromatography (SiO₂, heptane/EA) toafford the title compound as a white solid. MS (ES): M/Z [M+NH₄]=417. 1HNMR: (400 MHz, CDCl₃): 2.13 (s, 3H), 2.26 (s, 3H), 7.60 (bs, 1H) and7.73 (bs, 1H). 19F NMR (376 MHz, CDCl₃): −44.25 (s, 3F) and −63.63 (s,3F).

Preparation of3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methyl-4-trifluoromethylthiopyrazoleis described in Example 1.

Example 143-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methyl-4-trifluoromethylsulfinylpyrazole(Compound No 5)

A 30 wt % aqueous solution of hydrogen peroxide (29 μL) was added to atrifluoroacetic acid solution of3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methyl-4-trifluoromethylthiopyrazole(116 mg) described in Example 1. The reaction mixture was stirredovernight whereupon solvent was evaporated under reduced pressure togive a residue that was purified by chromatography (SiO₂, heptane/EA) toafford the title compound as a white solid (100 mg, 83%). MS (ES): M/Z[M+NH₄]=453. 1H NMR: (400 MHz, DMSO-d₆): 2.35 (s, 3H) and 8.41 (s, 2H).19F NMR (376 MHz, DMSO-d₆): −62.01 (s, 3F) and −74.18 (s, 3F).

Example 151-(2-Chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-5-methyl-4-trifluoromethylsulfinylpyrazole(Compound No 9)

Using a procedure similar to that described in Example 14, exceptstarting from1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-5-methyl-4-trifluoromethylthiopyrazoledescribed in Example 2, the title compound was isolated as a whitesolid. 1H NMR: (400 MHz, CDCl₃): 2.45 (bs, 3H), 7.59 (d, J=8.3 Hz, 1H)and 7.76 (s, 1H). 19F NMR (376 MHz, CDCl₃): −63.84 (s, 3F), −73.85 (d,3F) and −113.29 (dd, 1F).

Example 163-Cyano-1-(2,6-difluoro-4-trifluoromethylphenyl)-5-methyl-4-trifluoromethylsulfinylpyrazole(Compound No 12)

Using a procedure similar to that described in Example 14, exceptstarting from3-cyano-1-(2,6-difluoro-4-trifluoromethylphenyl)-5-methyl-4-trifluoromethylthiopyrazoledescribed in Example 12, the title compound was isolated as a whitesolid. 1H NMR: (400 MHz, CDCl₃): 2.50 (s, 3H) and 7.51 (d, 2H). 19F NMR(376 MHz, CDCl₃): −63.96 (s, 3F), −73.63 (s, 3F) and −114.52 to −114.76(d, 2F).

Example 173-Cyano-1-(2-fluoro-4-trifluoromethylphenyl)-5-methyl-4-trifluoromethylsulflnylpyrazole(Compound No 14)

Using a procedure similar to that described in Example 14, exceptstarting from3-cyano-1-(2-fluoro-4-trifluoromethylphenyl)-5-methyl-4-trifluoromethylthiopyrazoledescribed in Example 3, the title compound was isolated as a whitesolid.

Example 183-Cyano-1-(2,6-dichloro-4-trifluoromethoxyphenyl)-5-methyl-4-trifluoromethylsulfinylpyrazole(Compound No 19)

Using a procedure similar to that described in Example 14, exceptstarting from3-cyano-1-(2,6-dichloro-4-trifluoromethoxyphenyl)-5-methyl-4-trifluoromethylthiopyrazoledescribed in Example 6, the title compound was isolated as a whitesolid. MS (ES): M/Z [M+H] 452. 1H NMR: (400 MHz, DMSO-d₆): 2.34 (s, 3H)and 8.10 (m, 2H). 19F NMR (376 MHz, DMSO-d₆): −57.40 (s, 3F) and −74.24(s, 3F).

Example 193-Cyano-4-dichlorofluoromethylsulfinyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methylpyrazole(Compound No 20)

Using a procedure similar to that described in Example 14, exceptstarting from3-cyano-4-dichlorofluoromethylthio-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methylpyrazoledescribed in Example 5, the title compound was isolated as a whitesolid. MS (ES): M/Z [M+NH₄] 485. 1H NMR: (400 MHz, DMSO-d₆): 2.39 (s,3H) and 8.40 (s, 2H). 19F NMR (376 MHz, DMSO-d₆): −61.99 (s, 3F) and−64.05 (s, 1F).

Example 203-Cyano-4-dichlorofluoromethylsulfinyl-1-(2,6-dichloro-4-trifluoromethoxyphenyl)-5-methylpyrazole(Compound No 24)

Using a procedure similar to that described in Example 14, exceptstarting from3-cyano-4-dichlorofluoromethylthio-1-(2,6-dichloro-4-trifluoromethoxyphenyl)-5-methylpyrazoledescribed in Example 7, the title compound was isolated as a whitesolid. MS (ES): M/Z [M+NH₄] 501. 1H NMR: (400 MHz, CDCl₃): 2.43 (s, 3H)and 7.45 (s, 2H). 19F NMR (376 MHz, CDCl₃): −58.25 (s, 3F) and −63.02(s, 1F).

Example 211-(2-Chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-4-dichlorofluoromethylsulfinyl-5-methylpyrazole(Compound No 29)

Using a procedure similar to that described in Example 14, exceptstarting from1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-4-dichlorofluoromethylthio-5-methylpyrazoledescribed in Example 4, the title compound was isolated as a whitesolid. MS (ES): M/Z [M+NH₄] 469. 1H NMR: (400 MHz, CDCl₃): 2.39 (s, 3H),7.51 (d, 1H) and 7.68 (s, 1H). 19F NMR (376 MHz, CDCl₃): −63.00 to−63.06 (d, 1F), −63.82 (s, 3F) and −113.01 to −113.30 (m, 1F).

Example 221-(2-Chloro-4-trifluoromethylphenyl)-3-cyano-4-dichlorofluoromethylsulfinyl-5-methylpyrazole(Compound No 30)

Using a procedure similar to that described in Example 14, exceptstarting from4-chlorodifluoromethylthio-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-5-fluoromethylpyrazoledescribed in Example 8, the title compound was isolated as a whitesolid. 1H NMR: (400 MHz, CDCl₃): 2.47 (s, 3H), 7.63 (d, 1H), 7.80 (d,1H) and 7.93 (s, 1H). 19F NMR (376 MHz, CDCl₃): −62.97 (bs, 1F), −63.54(s, 3F).

Example 234-Chlorodifluoromethylsulfinyl-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-5-methylpyrazole(Compound No 37)

Using a procedure similar to that described in Example 14, exceptstarting from4-chlorodifluoromethylthio-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-5-methylpyrazoledescribed in Example 10, the title compound was isolated as a whitesolid. MS (ES): M/Z [M+NH₄] 453. 1H NMR: (400 MHz, CDCl₃): 2.46 (s, 3H),7.59 (dd, J=8.3, 1.5 Hz 1H) and 7.76 (bs, 1H). 19F NMR (376 MHz, CDCl₃):−60.68 to −62.28 (m, 2F), −63.83 (s, 3F) and −112.99 to 113.31 (m, 1F).

Example 241-(2-Chloro-6-methyl-4-trifluoromethylphenyl)-3-cyano-5-methyl-4-trifluoromethylsulfinylpyrazole(Compound No 44)

Using a procedure similar to that described in Example 14, exceptstarting from1-(2-chloro-6-methyl-4-trifluoromethylphenyl)-3-cyano-5-methyl-4-trifluoromethylthiopyrazoledescribed in Example 13, the title compound was isolated as a whitesolid. MS (ES): M/Z [M+NH₄] 433. 1H NMR: (400 MHz, CDCl₃): 2.15 (s, 3H),2.38 (s, 3H), 7.63 (bs, 1H) and 7.74 (bs, 1H). 19F NMR (376 MHz, CDCl₃):−63.67 (s, 3F) and −73.96 (s, 3F).

Example 253-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methyl-4-trifluoromethylsulfonylpyrazole(Compound No 4)

Sodium periodate (20 mg) and ruthenium chloride (3 mg) were added to asolution of3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methyl-4-trifluoromethylthiopyrazole(100 mg), that is described in Example 1, in a mixture ofacetonitrile-water (4:1). The reaction mixture was stirred overnightwhereupon the mixture was diluted with ethyl acetate and filtered oversilica gel. The organic filtrate was washed with water, dried overanhydrous magnesium sulfate, filtered over Celite and concentrated underreduced pressure to give the title compound as a white solid (73 mg,68%). MS (ES): M/Z [M+H]=452. 1H NMR: (400 MHz, DMSO-d₆): 2.46 (s, 3H)and 7.87 (s, 2H). 19F NMR (376 MHz, DMSO-d₆): −63.77 (s, 3F) and −79.83(s, 3F).

Example 261-(2-Chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-4-dichlorofluoromethylsulfonyl-5-methylpyrazole(Compound No 31)

Using a procedure similar to that described in Example 25, exceptstarting from1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-4-dichlorofluoromethylthio-5-methylpyrazoledescribed in Example 4, the title compound was isolated as a whitesolid. 1H NMR: (400 MHz, CDCl₃): 2.50 (bs, 3H), 7.61 (d, J=8.3 Hz, 1H)and 7.78 (bs, 1H). 19F NMR (376 MHz, CDCl₃): −63.77 (bs, 1F), −63.84 (s,3F) and −112.96 (bs, 1F).

Example 274-Chlorodifluoromethylsulfonyl-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-5-methylpyrazole(Compound No 39)

Using a procedure similar to that described in Example 25, exceptstarting from4-chlorodifluoromethylthio-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-5-methylpyrazoledescribed in Example 10, the title compound was isolated as a whitesolid. MS (ES): M/Z [M+NH₄] 469. 1H NMR: (400 MHz, CDCl₃): 2.49 (s, 3H),7.60-7.63 (m, 1H) and 7.78 (bs, 1H). 19F NMR (376 MHz, CDCl₃): −63.86(s, 3F), −64.87 (s, 2F) and −112.92 (m, 1F).

Example 283-Cyano-4-dichlorofluoromethylsulfonyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methylpyrazole(Compound No 41)

Using a procedure similar to that described in Example 25, exceptstarting from3-cyano-4-dichlorofluoromethylthio-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methylpyrazoledescribed in Example 5, the title compound was isolated as a whitesolid. MS (ES): M/Z [M+NH₄] 501. 1H NMR: (400 MHz, DMSO-d₆): 2.50 (s,3H) and 8.44 (s, 2H). 19F NMR (376 MHz, DMSO-d₆): −62.04 (s, 3F) and−65.19 (s, 1F).

The reaction scheme below depicts application of the general reactionscheme to synthesize compounds of Examples 1, 14 and 25.

Example 293-Cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-ethyl-4-trifluoromethylthiopyrazole(Compound No 2)

A solution of3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-(2-ethenyl)-4-trifluoromethylthiopyrazole(120 mg) in ethanol with catalytic amount of palladium on charcoal wascharged in a steel pressure vessel under a 50 psi hydrogen pressure andheated to 80° C. overnight. After cooling to room temperature themixture was filtered over Celite, and concentrated under reducedpressure to give a residue that was purified on reverse phase columnchromatography to give title compound as a white solid (39 mg, 32%). MS(ES): M/Z [M+H+ CH₃OH]=466. 1H NMR: (400 MHz, CDCl₃): 1.11 (t, 3H), 2.71(quartet, 2H) and 7.82 (s, 2H). 19F NMR (376 MHz, CDCl₃): −43.92 (s, 3F)and −63.68 (s, 3F).

The starting material,3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-(2-ethenyl)-4-trifluoromethylthiopyrazole,was prepared as follows:

-   -   a. A dioxane solution of        5-bromo-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole        (100 mg), prepared as described in EP-A-0 295 117, was        transferred via a syringe into a 10 ml sealed Pyrex glass tube        previously charged with cesium fluoride (30 mg),        tetrakis(triphenylphosphine)palladium (11 mg) and        vinyltributyltin (0.07 mL). The glass tube was heated in a        microwave for 10 minutes at 180° C. After cooling to room        temperature, the mixture was filtered over Celite, diluted with        ethyl acetate, washed with water and brine. The organic phase        was dried over anhydrous magnesium sulfate, filtered and        concentrated under reduced pressure to give a residue that was        purified on reverse phase column chromatography to give        3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-(2-ethenyl)-4-trifluoromethylthiopyrazole        as a white solid (24 mg, 28%). 1H NMR: (400 MHz, DMSO-d₆):        5.80-6.02 (m, 2H), 6.54-6.61 (mt, 1H) and 8.39 (s, 2H). 19F NMR        (376 MHz, DMSO-d₆): −43.65 (s, 3F) and −61.99 (s, 3F).        The reaction scheme below depicts application of this method to        prepare the compound described in Example 29:

Example 303-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-fluoromethyl-4-trifluoromethylthiopyrazole(Compound No 3)

Dimethylaminosulfur trifluoride (2.27 mL) was added to a solution of3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-hydroxymethyl-4-trifluoromethylthiopyrazole(2.9 g) in dichloromethane. After stirring for 3 hours, water was addedfollowed by dichloromethane. The organic phase was washed with anaqueous solution of saturated sodium bicarbonate, dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure togive a residue that was purified by chromatography (SiO₂, heptane/EA) toafford the title compound as a white solid (2.45 g, 84%). 1H NMR: (400MHz, CDCl₃): 5.38 (d, J=47.5 Hz, 2H) and 7.83 (s, 2H). 19F NMR (376 MHz,CDCl₃): −43.83 (s, 3F), −63.76 (s, 3F) and −84.12 (t, J=47.5 Hz, 1F).

The starting material,3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-hydroxymethyl-4-trifluoromethylthiopyrazole,was prepared as described below:

-   -   a. A solution of        5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole        (87.5 g), prepared as described in EP-A-0 295 117, was added        dropwise to a suspension of tert-butylnitrite (32 mL), methyl        acrylate (149 mL) and copper bromide (55.6 g) in acetonitrile.        The reaction mixture was stirred overnight. The resulting        mixture was diluted with diethylether and washed with water. The        organic layer was dried over anhydrous magnesium sulfate,        filtered and concentrated under reduced pressure. Trituration of        the residue from ethyl acetate and heptane gave        5-(2′-bromo-2′-carbomethoxy)ethyl-3-cyano-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-trifluoromethylthiopyrazole        as a tanned solid (73.7 g, 78%).    -   b. 1,8-diazabicyclo-[5.4.0]-undec-7-ene (4.4 mL) was added to a        solution of        5-(2′-bromo-2′-carbomethoxy)ethyl-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole        (15.1 g) dissolved in toluene. After stirring for 40 minutes,        the mixture was diluted with ethyl acetate, washed with water,        10% aqueous hydrochloric acid solution and water. The organic        phase was dried over anhydrous magnesium sulfate, filtered and        concentrated under reduced pressure to give        3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-(E-2-methoxycarbonylethenyl)-4-trifluoromethylthiopyrazole        as a white solid (11.0 g 85%).    -   c. Ozone was bubbled through a solution of the        3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-(E-2-methoxycarbonyl-ethenyl)-4-trifluoromethylthiopyrazole        (4.8 g) in dichloromethane and methanol for 3 h at −78° C. After        3 hours the intensely blue solution was decolorized with oxygen        gas, and then treated with dimethylsulfide at −78° C. This        reaction mixture was allowed to warm to room temperature        whereupon the mixture was washed with a 10% aqueous solution of        sodium bisulfate. The resulting mixture was extracted with ethyl        acetate. The organic layer was dried over anhydrous magnesium        sulfate, filtered and concentrated under reduced pressure to        give        3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-formyl-4-trifluoromethylthiopyrazole        as a white solid (4.2 g).    -   d.        3-Cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-formyl-4-trifluoromethylthiopyrazole        (4.2 g) was dissolved in absolute ethanol and sodium borohydride        (0.61 g) added portion wise at 0° C. This reaction mixture was        stirred and allowed to warm to room temperature over 2 h        whereupon water was added. The resulting mixture was extracted        with ethyl acetate. The organic layer was dried over anhydrous        magnesium sulfate, filtered and concentrated under reduced        pressure to give a residue that was purified by chromatography        (SiO₂, heptane/EA) to afford        3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-hydroxymethyl-4-trifluoromethylthiopyrazole        as a white solid (4.03 g, 94%).

Example 311-(2-Chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-5-fluoromethyl-4-trifluoromethylthiopyrazole(Compound No 8)

Using a procedure similar to that described in Example 30, exceptstarting from1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-5-hydroxymethyl-4-trifluoromethylthiopyrazole,the title compound was isolated as a white solid. 1H NMR: (400 MHz,DMSO-d₆): 5.46-5.67 (m, 2H) and 8.41 (m, 2H). 19F NMR (376 MHz,DMSO-d₆): −43.57 (s, 3F), −62.14 (s, 3F), −82.55 (t, J=47 Hz, 1F) and−114.79 (m, 1F).

The starting material,1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-5-hydroxymethyl-4-trifluoromethylthiopyrazole,was prepared following a similar procedure to that described in Example30, steps a,b,c,d from5-amino-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthiopyrazole,prepared as follows:

-   -   a. N-Chlorosuccinimide (4.1 g) was added to a solution of        2-fluoro-4-trifluoromethylaniline in acetonitrile under nitrogen        and the mixture heated to 75° C. over night. The mixture was        concentrated, diluted with ether, washed with water, saturated        sodium bicarbonate solution and brine. The organic layers were        dried over anhydrous magnesium sulfate, filtered and        concentrated under reduced pressure to give        2-chloro-6-fluoro-4-trifluoromethylaniline as a liquid (5.9 g).        Rf=0.6 (2:8 EA/heptane); 1H NMR: (400 MHz, CDCl₃) 4.41 (bs, 2H);        7.20 (dd, 1H, J=10.5, 1.5 Hz) and 7.36 (s, 1H). 19F NMR (376        MHz, CDCl₃): −130.78 (s, 1F) and −61.98 (s, 3F).    -   b. A solution of 2-chloro-6-fluoro-4-trifluoromethylaniline        (5 g) in acetic acid was added dropwise to a suspension of        nitrosyl sulphuric acid (11.2 g) in acetic acid at 15° C. After        stirring for 1 hour, this reaction mixture was added dropwise to        a suspension of 1,2-dicyano-3-hydroxyprop-2-ene potassium salt        (10 g) and sodium acetate trihydrate (32 g) in a mixture of        sodium acetic and water at 7° C. After stirring for 1 hour, this        reaction mixture was diluted with water and extracted with        dichloromethane. The organic layers were stirred vigorously with        a 30% ammonium hydroxide solution for 10 minutes, separated,        dried over anhydrous magnesium sulfate, filtered and        concentrated under reduced pressure to give a residue that was        purified by chromatography (SiO₂, heptane/EA) to afford        5-amino-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyanopyrazole        as a yellow-orange solid (5.1 g, 71%). R_(f)=0.25 (3:7        EA/heptane); 1H NMR (400 MHz, DMSO-d₆): 5.94 (s, 1H), 6.14 (s,        2H) and 8.06-8.10 (m, 2H). 19F NMR (376, DMSO-d₆): −61.98 (s,        3F) and −114.38 (s, 1F).

The 1,2-dicyano-3-hydroxyprop-2-ene potassium salt was prepared asfollows:

A solution of potassium tert-butoxide (29 g) in tert-butanol was addeddropwise to a solution of succinonitrile (20 g) and ethyl formate (22.7g) in a 5:1 mixture of toluene and tert-butanol at 5° C. After stirringfor 6 hours, the solid was filtered off, washed once with ethanol andthree times with methyl tert-butyl ether and then dried over night in avacuum oven at 55° C. to give 1,2-dicyano-3-hydroxyprop-2-ene potassiumsalt as a tan solid (35 g, 96%).

-   -   c. A solution of        5-amino-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyanopyrazole        (3 g) in dichloromethane was stirred at 0° C. and treated        dropwise with a solution of trifluoromethylsulphenyl chloride        (2 g) in dichloromethane during 1 hour. After stirring overnight        at room temperature, nitrogen was bubbled trough the solution        for 5 minutes. Then the mixture was washed with water, saturated        sodium bicarbonate solution and brine. The organic layers were        dried over anhydrous magnesium sulfate, filtered and        concentrated under reduced pressure to give a residue that was        purified by chromatography (SiO₂, heptane/EA) to afford        5-amino-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthiopyrazole        as a white solid (3.5 g, 86%). R_(f)=0.4 (3:7 EA/heptane); 1H        NMR (400 MHz, DMSO-d₆) 7.21 (bs, 2H) and 8.10-8.14 (m, 2H). 19F        NMR (376 MHz, DMSO-d₆): −45.33 (s, 3F), −62.08 (s, 3F) and        −114.62 (s, 1F).

Example 323-Cyano-1-(2,6-dichloro-4-trifluoromethoxyphenyl)-5-fluoromethyl-4-trifluoromethylthiopyrazole(Compound No 16)

Using a procedure similar to that described in Example 30, exceptstarting from3-cyano-1-(2,6-dichloro-4-trifluoromethoxyphenyl)-5-hydroxymethyl-4-trifluoromethylthiopyrazole,the title compound was isolated as a white solid. MS (ES): M/Z [M+H]454. 1H NMR: (400 MHz, DMSO-d₆): 5.47 (d, J=46 Hz, 2H) and 8.09 (s, 2H).19F NMR (376 MHz, DMSO-d₆): −43.67 (s, 3F), −57.37 (s, 3F) and −82.82(t, J=45 Hz, 1F).

The starting material,3-cyano-1-(2,6-dichloro-4-trifluoromethoxyphenyl)-5-hydroxymethyl-4-trifluoromethylthiopyrazole,was prepared following a similar procedure to that described in Example30, steps a,b,c,d, from5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethoxyphenyl)-4-trifluoromethylthiopyrazolethat is described in EP-A-0 295 117.

Example 331-(2-Chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-4-dichlorofluoromethylthio-5-fluoromethylpyrazole(Compound No 25)

Using a procedure similar to that described in Example 30, exceptstarting from1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-4-dichlorofluoromethylthio-5-hydroxymethylpyrazole,the title compound was isolated as a white solid. 1H NMR: (400 MHz,CDCl₃): 5.29-5.54 (m, 2H), 7.57 (dd, J=8, 1.5 Hz, 1H) and 7.74 (bs, 1H).19F NMR (376 MHz, CDCl₃): −21.99 (s, 1F), −37.00 (t, J=47 Hz, 1F),−63.81 (s, 3F) and −113.28 (bs, 1F).

The starting material,1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-4-dichlorofluoromethylthio-5-hydroxymethylpyrazole,was prepared following a similar procedure to that described in Example30, steps a,b,c,d, from5-amino-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-4-dichlorofluoromethylthiopyrazole,prepared as follows:

-   -   a. Sulfur monochloride (0.78 g) was added at 10° C. to a        dichloromethane solution of        5-amino-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyanopyrazole        (3.54 g), described in Example 31 step b. After stirring        overnight at room temperature, nitrogen was bubbled trough the        solution for 5 minutes. The solid precipitate was filtered,        washed with dichloromethane, heptane and dried under reduced        pressure to give        5-amino-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyanopyrazol-4-yl        disulfide as a pale yellow solid (2.8 g, 72%). R_(f)=0.3 (4:6        EA/heptane)    -   b. Sodium dithionite (6.2 g), disodium hydrogen phosphate        (4.3 g) and fluorotrichloromethane (5.2 g) were added with        stirring to a solution of        5-amino-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyanopyrazol-4-yl        disulfide (5.15 g) in a 2:1 mixture of N,N-dimethylformamide and        water at 15° C. After stirring for one hour, the mixture was        poured into ice and stirred for 30 minutes. The solid was        filtered off, washed with water and dried to give        5-amino-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-4-dichlorofluoromethylthiopyrazole        as a white solid (4.1 g, 64%). R_(f)=0.4 (3:7 EA/heptane).

Example 343-Cyano-4-dichlorofluoromethylthio-1-(2,6-dichloro-4-trifluoromethoxyphenyl)-5-fluoromethylpyrazole(Compound No 21)

Using a procedure similar to that described in Example 30, exceptstarting from3-cyano-4-dichlorofluoromethylthio-1-(2,6-dichloro-4-trifluoromethoxyphenyl)-5-hydroxymethylpyrazole,the title compound was isolated as a white solid. 1H NMR: (400 MHz,DMSO-d₆): 5.59 (d, J=46 Hz, 2H) and 8.10 (s, 2H). 19F NMR (376 MHz,DMSO-d₆): −21.31 (s, 1F), −57.36 (s, 3F) and −83.08 (t, J=45 Hz, 1F).

The starting material,3-cyano-4-dichlorofluoromethylthio-1-(2,6-dichloro-4-trifluoromethoxyphenyl)-5-hydroxymethylpyrazole,was prepared following a similar procedure to that described in Example30, steps a,b,c,d, from5-amino-3-cyano-4-dichlorofluoromethylthio-1-(2,6-dichloro-4-trifluoromethoxyphenyl)pyrazole,which was prepared following a similar procedure to that described inExample 33, steps a,b, from5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethoxyphenyl)pyrazole thatitself was prepared from 2,6-dichloro-4-trifluoromethoxyaniline using asimilar procedure to that described in Example 31, steps b,c.

Example 353-Cyano-1-(2,6-dichloro-4-pentafluorothiophenyl)-5-fluoromethyl-4-trifluoromethylthiopyrazole(Compound No 33)

Using a procedure similar to that described in Example 30, exceptstarting from3-cyano-1-(2,6-dichloro-4-pentafluorothiophenyl)-5-hydroxymethyl-4-trifluoromethylthiopyrazole,the title compound was isolated as a white solid. 1H NMR: (400 MHz,CDCl₃): 5.39 (d, J=47 Hz, 2H) and 7.96 (s, 2H). 19F NMR (376 MHz,CDCl₃): −43.76 (s, 3F), 62.68 (d, J=151 Hz, 4F) and 78.84 (quintet,J=150 Hz, 1F).

The starting material,3-cyano-1-(2,6-dichloro-4-pentafluorothiophenyl)-5-hydroxymethyl-4-trifluoromethylthiopyrazole,was prepared following a similar procedure to that described in Example30, steps a,b,c,d, from5-amino-3-cyano-1-(2,6-dichloro-4-pentafluorothiophenyl)-4-trifluoromethylthiopyrazole,prepared from 4-pentafluorothioaniline following a similar procedure tothat described in Example 31, steps a,b,c, except that 2.2 equivalentsof N-chlorosuccinimide were used in step a.

Example 364-Chlorodifluoromethylthio-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-5-fluoromethylpyrazole(Compound No 35)

Using a procedure similar to that described in Example 30, exceptstarting from4-chlorodifluoromethylthio-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-5-hydroxymethylpyrazole,the title compound was isolated as a white solid. MS (ES): M/Z [M−H]436. 1H NMR: (400 MHz, CDCl₃): 5.29-5.54 (m, 2H), 7.57 (dd, J=8.3, 1.5Hz, 1H) and 7.74 (bs, 1H). 19F NMR (376 MHz, CDCl₃): −63.83 (s, 3F),−84.17 (t, J=47 Hz, 1F), −113.31 (s, 1F) and −162.04 (s, 2F).

The starting material,4-chlorodifluoromethylthio-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-5-hydroxymethylpyrazole,was prepared following a similar procedure to that described in Example30, steps a,b,c,d, from5-amino-4-chlorodifluoromethylthio-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyanopyrazole,prepared following the same procedure to that described in Example 33,steps a,b, except that bromochlorodifluoromethane was used in step binstead of fluorotrichloromethane.

Example 373-Cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-fluoromethyl-4-trifluoromethylsulfinylpyrazole(Compound No 10)

A 30 wt % aqueous solution of hydrogen peroxide (50 μL) was added to atrifluoroacetic acid solution of3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-fluoromethyl-4-trifluoromethylthiopyrazole(205 mg) prepared as described in Example 30. The reaction mixture wasstirred for 6 h whereupon solvent was evaporated under reduced pressureto give a residue that was purified by chromatography (SiO₂,heptane/DCM) to afford the title compound as a white solid (66.5 mg,32%). MS (ES): M/Z [M−H] 452. 1H NMR: (400 MHz, DMSO-d₆): 5.48-5.75 (m,2H) and 8.41 (s, 2H). 19F NMR (376 MHz, DMSO-d₆): −62.05 (s, 3F), −73.68(d, 3F) and −82.41 (m, 1F).

Example 381-(2-Chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-5-fluoromethyl-4-trifluoromethylsulfinylpyrazole(Compound No 11)

Using a procedure similar to that described in Example 37, exceptstarting from1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-5-fluoromethyl-4-trifluoromethylthiopyrazoledescribed in Example 31, the title compound was isolated as a whitesolid. MS (ES): M/Z [M+H] 438. 1H NMR: (400 MHz, DMSO-d₆): 5.48-5.77 (m,2H) and 8.26 (m, 2H). 19F NMR (376 MHz, DMSO-d₆): −62.17 (s, 3F), −73.63(bs, 3F), −82.18 (m, 1F) and −114.50 to −114.84 (m, 1F).

Example 393-Cyano-1-(2,6-dichloro-4-trifluoromethoxyphenyl)-5-fluoromethyl-4-trifluoromethylsulfinylpyrazole(Compound No 18)

Using a procedure similar to that described in Example 37, exceptstarting from3-cyano-1-(2,6-dichloro-4-trifluoromethoxyphenyl)-5-fluoromethyl-4-trifluoromethylthiopyrazoledescribed in Example 32, the title compound was isolated as a whitesolid. MS (ES): M/Z [M+H] 470. 1H NMR: (400 MHz, DMSO-d₆): 5.46-5.74 (m,2H) and 8.10 (m, 2H). 19F NMR (376 MHz, DMSO-d₆): −57.37 (s, 3F), −73.72(s, 3F) and −82.46 (t, J=46 Hz, 1F).

Example 403-Cyano-4-dichlorofluoromethylsulfinyl-1-(2,6-dichloro-4-trifluoromethoxyphenyl)-5-fluoromethylpyrazole(Compound No 22)

Using a procedure similar to that described in Example 37, exceptstarting from3-cyano-4-dichlorofluoromethylthio-1-(2,6-dichloro-4-trifluoromethoxyphenyl)-5-fluoromethylpyrazoledescribed in Example 33, the title compound was isolated as a whitesolid. MS (ES): M/Z [M+NH₄] 519. 1H NMR: (400 MHz, CDCl₃): 5.50-5.72 (m,2H) and 7.44 (s, 2H). 19F NMR (376 MHz, CDCl₃): −58.25 (s, 3F), −63.63(s, 1F) and −85.23 (t, 1F).

Example 411-(2-Chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-4-dichlorofluoromethylsulfinyl-5-fluoromethylpyrazole(Compound No 28)

Using a procedure similar to that described in Example 37, exceptstarting from1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-4-dichlorofluoromethylthio-5-fluoromethylpyrazoledescribed in Example 34, the title compound was isolated as a whitesolid. MS (ES): M/Z [M+NH₄] 487. 1H NMR: (400 MHz, CDCl₃): 5.20-5.87 (m,2H), 7.58 (d, 1H) and 7.74 (s, 1H). 19F NMR (376 MHz, CDCl₃): −63.59 to−63.69 (d, 1F), −63.83 (s, 3F) and −112.95 to −113.38 (m, 1F).

Example 424-Chlorodifluoromethylsulfinyl-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-5-fluoromethylpyrazole(Compound No 38)

Using a procedure similar to that described in Example 37, exceptstarting from4-chlorodifluoromethylthio-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-5-fluoromethylpyrazoledescribed in Example 35, the title compound was isolated as a whitesolid. MS (ES): M/Z [M+NH₄] 471. 1H NMR: (400 MHz, CDCl₃): 5.45-5.82 (m,2H), 7.57 (d, J=8.2 Hz, 1H) and 7.74 (s, 1H). 19F NMR (376 MHz, CDCl₃):−8.59 to −8.91 (m, 1F), −60.81 to −62.41 (m, 2F), −63.84 (s, 3F) and−112.99 to −113.35 (m, 1F).

Example 431-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-4-dichlorofluoromethylsulfonyl-5-fluoromethylpyrazole(Compound No 32)

Sodium periodate (100 mg) and ruthenium chloride (3 mg) were added to asolution of1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-4-dichlorofluoromethylthio-5-fluoromethylpyrazole(100 mg), prepared as described in Example 33, in a mixture ofacetonitrile-water (2:1). The reaction mixture was stirred overnightwhereupon the mixture was diluted with ethyl acetate and saturatedaqueous sodium bicarbonate. The organic extract was separated, filteredover Celite and concentrated under reduced pressure to give the titlecompound as a white solid. MS (ES): M/Z [M+NH₄] 503. 1H NMR: (400 MHz,CDCl₃): 5.48-5.77 (m, 2H), 7.60 (dd, J=8.3, 1.4 Hz, 1H) and 7.77 (bs,1H). 19F NMR (376 MHz, CDCl₃): −63.77 (bs, 1F), −63.86 (s, 3F), −87.74to −87.99 (m, 1F) and −113.09 (m, 1F).

Example 444-Chlorodifluoromethylsulfonyl-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-5-fluoromethylpyrazole(Compound No 40)

Using a procedure similar to that described in Example 43, exceptstarting from4-chlorodifluoromethylthio-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-5-fluoromethylpyrazoledescribed in Example 36, the title compound was isolated as a whitesolid. MS (ES): M/Z [M+NH₄] 487. 1H NMR: (400 MHz, CDCl₃): 5.46-5.74 (m,2H), 7.61 (dd, J=8.3, 1.6 Hz, 1H) and 7.77 (bs, 1H). 19F NMR (376 MHz,CDCl₃): −10.69 (t, J=47 Hz, 1F), −63.87 (bs, 3F), −64.56 (s, 2F) and−113.04 (m, 1F).

The reaction scheme below depicts application of the general reactionscheme to synthesize compounds of Examples 30, 37 and 43.

Example 451-(2-Chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-4-dichlorofluoromethylthio-5-difluoromethylpyrazole(Compound No 45)

A mixture of1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-4-dichlorofluoromethylthio-5-formylpyrazole(450 mg) and [bis(2-methoxyethyl)amino]sulfur trifluoride (660 mg) indichloromethane was heated to reflux for 6 h, then was cooled to roomtemperature and evaporated. The residue was purified by chromatography(SiO₂, heptane/DCM) to afford the title compound as a white solid (210mg, 44%). 1H NMR: (400 MHz, CDCl₃): 6.88 (t, J=51.5 Hz, 1H), 7.55 (dd,J=8.3, 1.6 Hz, 1H), 7.72 (s, 1H). 19F NMR: (376 MHz, CDCl₃): −20.6 (s,1F), −63.8 (s, 3F), −112.8 (s, 1H), −115.9 to −118.0 (m, 2F).

The starting material,1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-4-dichlorofluoromethylthio-5-formylpyrazole,was prepared using a procedure similar to that described in Example 30,parts a, b and c from5-amino-1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthiopyrazole,prepared as described in Example 31, parts a, b and c.

Example 461-(2-Chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-4-dichlorofluoromethylsulfinyl-5-difluoromethylpyrazole(Compound No 46)

Using a procedure similar to that described in Example 37, exceptstarting from1-(2-chloro-6-fluoro-4-trifluoromethylphenyl)-3-cyano-4-dichlorofluoromethylthio-5-difluoromethylpyrazoledescribed in Example 45, the title compound was isolated as a whitesolid. 1H NMR: (400 MHz, CDCl₃): 7.40 (dd, J=51.9, 8.0 Hz, 1H), 7.56(dd, J=8, 1.5 Hz, 1H), 7.73 (d, J=1.5 Hz, 1H). 19F NMR: (376 MHz,CDCl₃): −63.3 (d, J=39 Hz, 1F), −63.9 (s, 3F), −112.1 to −112.8 (m, 1F),−116.2 to −116.7 (m, 2F).

The reaction scheme below depicts application of this method tosynthesize compounds of Examples 45 and 46:

Example 471-[3-Chloro-5-(trifluoromethyl)-2-pyridinyl]-3-cyano-4-dichlorofluoromethylthio-5-methylpyrazole(Compound 47)

A 30 wt % aqueous ammonium hydroxide solution (50 mL) was added to anethanol solution (150 mL) of1-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]-4-dichlorofluoromethylthio-3-ethoxycarbonyl-5-methylpyrazole(9.0 g). After one week stirring at room temperature, solvent wasevaporated under reduced pressure to give a solid residue that wasdissolved in methanol (40 mL) and treated with more ammonium hydroxidesolution (30% aqueous, 12 mL). After 3 days, solvent was partiallyremoved under reduced pressure to give a mixture containing solids thatwere filtered off. The collected solids were washed with water and driedto give a white solid that was used in the next step without furtherpurification (6.25 g, 74%). Rf=0.2 (3:7 EA/heptane). 1H NMR (400 MHz,CDCl₃): 8.82 (d, J=1.3 Hz, 1H), 8.26 (d, J=2.0 Hz, 1H), 6.80 (br s, 1H),5.77 (br s, 1H) and 2.46 (s, 3H). 19F NMR (376 MHz, CDCl₃): −62.69 (s,3F) and −153.47 (s, 1F).

Oxalyl chloride (4.3 mL) was added dropwise to a stirred solution ofN,N-dimethylformamide (3.7 mL) in acetonitrile (150 mL) at 0° C. Afterstirring for 10 minutes, a solution of the above white solid inacetonitrile (60 mL) was added dropwise and the reaction mixture wasstirred 1 h. allowing it to warm to room temperature. The reactionmixture was poured rapidly into stirring ice water, stirred 30 minutesand the resulting solid filtered, washed with water and dried to givethe title compound as a white solid (5.35 g, 93%). Rf=0.6 (3:7EA/heptane). MS (ES): M/Z [M+H]=419. 1H NMR (400 MHz, CDCl₃): 8.82 (d,J=1.3 Hz, 1H), 8.28 (d, J=2.0 Hz, 1H) and 2.47 (s, 3H). 19F NMR (376MHz, CDCl₃): −21.25 (s, 1F) and −62.69 (s, 3F).

The starting material,1-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]-4-dichlorofluoromethylthio-3-ethoxycarbonyl-5-methylpyrazole,was prepared as follows:

Potassium carbonate (7.0 g) was added as a solid to a solution of4-dichlorofluoromethylthio-3-ethoxycarbonyl-5-methyl-1-H-pyrazole (7.25g) and 2,3-dichloro-5-(trifluoromethyl)pyridine (5.9 g) indimethoxyethane (100 mL). The mixture was heated to reflux overnight,cooled to room temperature and filtered over a pad of celite. Thefiltrate was concentrated under reduced pressure to give a residue thatwas purified by chromatography (SiO₂, heptane/EA) to afford1-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]-4-dichlorofluoromethylthio-3-ethoxycarbonyl-5-methylpyrazoleas a white solid (9.0 g, 76%). Rf=0.8 (1:1 EA/heptane). 1H NMR (400 MHz,CDCl₃): 8.82 (d, 1H), 8.23 (d, J=1.7 Hz, 1H), 4.47 (q, J=7.1 Hz, 2H),2.45 (s, 3H) and 1.42 (t, J=7.1 Hz, 3H). 19F NMR (376 MHz, CDCl₃):−20.43 (s, 1F) and −62.70 (s, 3F).

Example 481-(6-Chloro-4-trifluoromethylpyrid-2-yl)-3-cyano-4-dichlorofluoromethylsulfinyl-5-methylpyrazole(Compound No. 48)

A 30 wt % aqueous hydrogen peroxide solution (550 μL) was added tosolution of1-(6-chloro-4-trifluoromethyl-pyrid-2-yl)-3-cyano-5-methyl-4-fluorodichloromethylthiopyrazole(9.0 g) in a trifluoroacetic (15 mL) and dichloromethane (30 mL) andstirred at room temperature overnight. Water was added (50 mL), followedby sodium carbonate till neutral pH was reached. Mixture was extractedwith dichloromethane (100 mL). The organic layer was washed withsaturated sodium thiosulfate solution and then water, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to give a residue that was purified by chromatography (SiO₂,heptane/EA) to afford1-(6-chloro-4-trifluoromethylpyrid-2-yl)-3-cyano-4-dichlorofluoromethylsulfinyl-5-methylpyrazoleas a white solid (1.15 g, 55%). MS (ES): M/Z [M+NH₄]=452. 1H NMR (400MHz, CDCl₃): 8.84 (s, 1H), 8.30 (1, 1H) and 2.57 (s, 3H). 19F NMR (376MHz, CDCl₃): −62.74 (s, 3F) and −62.85 (s, 1F).

Additional 1-aryl-5-alkyl pyrazole and 1-aryl-3,4,5 pyrazole compoundsmay be prepared by the process of the invention. Example embodiments ofthe compounds are described in Table 1 below.

TABLE 1 (I)

Compound # R₁ R₂ R₃ R₄ R₆ Z 1 CN SCF₃ CH₃ Cl CF₃ C—Cl 2 CN SCF₃ CH₂CH₃Cl CF₃ C—Cl 3 CN SCF₃ CH₂F Cl CF₃ C—Cl 4 CN S(O)₂CF₃ CH₃ Cl CF₃ C—Cl 5CN S(O)CF₃ CH₃ Cl CF₃ C—Cl 6 CN SCF₃ CH₃ F CF₃ C—F 7 CN SCF₃ CH₃ Cl CF₃C—F 8 CN SCF₃ CH₂F Cl CF₃ C—F 9 CN S(O)CF₃ CH₃ Cl CF₃ C—F 10 CN S(O)CF₃CH₂F Cl CF₃ C—Cl 11 CN S(O)CF₃ CH₂F Cl CF₃ C—F 12 CN S(O)CF₃ CH₃ F CF₃C—F 13 CN SCF₃ CH₃ H CF₃ C—F 14 CN S(O)CF₃ CH₃ H CF₃ C—F 15 CN SCCl₂FCH₃ Cl CF₃ C—Cl 16 CN SCF₃ CH₂F Cl OCF₃ C—Cl 17 CN SCF₃ CH₃ Cl OCF₃ C—Cl18 CN S(O)CF₃ CH₂F Cl OCF₃ C—Cl 19 CN S(O)CF₃ CH₃ Cl OCF₃ C—Cl 20 CNS(O)CCl₂F CH₃ Cl CF₃ C—Cl 21 CN SCCl₂F CH₂F Cl OCF₃ C—Cl 22 CN S(O)CCl₂FCH₂F Cl OCF₃ C—Cl 23 CN SCCl₂F CH₃ Cl OCF₃ C—Cl 24 CN S(O)CCl₂F CH₃ ClOCF₃ C—Cl 25 CN SCCl₂F CH₂F Cl CF₃ C—F 26 CN SCCl₂F CH₃ Cl CF₃ C—F 27 CNSCCl₂F CH₃ H CF₃ C—Cl 28 CN S(O)CCl₂F CH₂F Cl CF₃ C—F 29 CN S(O)CCl₂FCH₃ Cl CF₃ C—F 30 CN S(O)CCl₂F CH₃ H CF₃ C—Cl 31 CN S(O)₂CCl₂F CH₃ ClCF₃ C—F 32 CN S(O)₂CCl₂F CH₂F Cl CF₃ C—F 33 CN SCF₃ CH₂F Cl SF₅ C—Cl 34CN SCF₃ CH₃ Cl SF₅ C—Cl 35 CN SCClF₂ CH₂F Cl CF₃ C—F 36 CN SCClF₂ CH₃ ClCF₃ C—F 37 CN S(O)CClF₂ CH₃ Cl CF₃ C—F 38 CN S(O)CClF₂ CH₂F Cl CF₃ C—F39 CN S(O)₂CClF₂ CH₃ Cl CF₃ C—F 40 CN S(O)₂CClF₂ CH₂F Cl CF₃ C—F 41 CNS(O)₂CCl₂F CH₃ Cl CF₃ C—Cl 42 CN SCCl₂F CH₃ Cl SF₅ C—Cl 43 CN SCF₃ CH₃Cl CF₃ C—CH₃ 44 CN S(O)CF₃ CH₃ Cl CF₃ C—CH₃ 45 CN SCCl₂F CHF₂ Cl CF₃ C—F46 CN S(O)CCl₂F CHF₂ Cl CF₃ C—F 47 CN SCCl₂F CH₃ Cl CF₃ N 48 CNS(O)CCl₂F CH₃ Cl CF₃ N

Method of Use Examples

METHOD A: Screening Method to Test Contact Activity of Compounds AgainstTicks

A solution of the test compound was used to coat the inner wall of glassvials and to treat two filter papers. Once dried, one filter paper wasplaced in the cap of the vial and the other in the bottom of the vial.Each treated vial was infested with 10 adult Rhipicephalus sanguineus(Brown Dog Tick). Contact of the ticks with residues was induced byholding the vials in a controlled environment (24° C., 90-95% relativehumidity) and assessment was performed at 24, 48 hours after applicationin comparison with untreated controls. Compounds numbers 1, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19, 20, 22, 24, 25, 26, 28, 29,31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 43 and 44 gave at least 80%control of Rhipicephalus sanguineus at the 48 hour assessment, at a testconcentration of 25 ppm or less; and had LD₅₀ values below 6 ppm at the48 hour assessment.

METHOD B: Screening Method to Test Contact Activity of Compounds AgainstFleas

A solution of the test compound was dispensed, using a pipette, ontofilter paper placed into a glass vial. The filter paper was allowed todry before infesting each vial with 10 adult Ctenocephalides felis. Thetreated Ctenocephalides felis were held in a controlled environment (24°C., 90-95% relative humidity) and assessment was performed at 24, 48 and72 hours after application in comparison with untreated controls.Compounds numbers 1, 6, 7, 15, 20, 21, 23, 25, 26, 28, 29, 31, 32, 33,34, 35, 36, 37, 39, 40 and 42 gave at least 80% control at 72 hoursassessment at a test concentration of 25 ppm or less; and had LD₅₀values below 12 ppm at 72 hours assessment. By way of comparisonfipronil (the active ingredient in Frontline®, a known product used tocombat fleas), used as a positive control, had an LD₅₀ value around 20ppm at the 72 hour assessment.

METHOD C: Screening Method to Test Activity of Compounds Against FleasFollowing Ingestion

A cylindrical test container was filled with 10 adult Ctenocephalidesfelis. A cylindrical well was closed on one end with a self-sealingflexible film and placed on top of the test container in such a positionthat the fleas could pierce the film and feed on the contents of thecylinder. The test compound solution was then pipetted into bovine bloodand added to the well. The container part with the Ctenocephalides feliswas held at 20-22° C. and 40-60% relative humidity while the well partcontaining the treated blood was held at 37° C. and 40-60% relativehumidity. Assessment was performed at 72 hours after application incomparison with untreated controls. Compounds numbers 1, 5, 6, 7, 9, 15,20, 25, 26, 28, 29, 31, 32, 33, 34, 41 and 42 gave at least 80% controlat a test concentration of 2.5 ppm or less; and had an LD₅₀ values below1.5 ppm at the 72 hour assessment.

METHOD D: Screening Method to Test Activity of Compounds AgainstHeliothis virescens.

Experimental compounds were diluted in acetone. Using a syringe, 1 μl ofthe test solution was applied to the thorax of susceptible, third instarHeliothis virescens larvae. Larvae were then placed on artificial dietand held at 27° C. and 50-70% relative humidity. Mortality was assessedover a five day period. Larvae treated with acetone only served ascontrols. At the 5 days assessment, compounds numbers 26 and 29 gave atleast 50% control of Heliothis virescens at a test concentration of 260μgram active ingredient per gram of insect.

METHOD E: Screening Method to Test Activity of Compounds AgainstLeptinotarsa decemlineata.

Experimental compounds were diluted in an aqueous formulation containing5% DMSO and 0.1% Triton X100. Leaf discs with a 3 cm diameter were cutfrom leaves of Solanum tuberosum and dipped in the formulations. Afterdrying, two treated leaf discs were placed into a test plate containing2% water agar. Discs treated with 5% DMSO, 0.1% Triton X100 served ascontrols. Ten susceptible adult Leptinotarsa decemlineata were thenadded to each test plate. The test plates were then held at 27° C. for24 hours during which time the L. decemlineata were assessed forknockdown, mortality and leaf consumption. Compounds numbers 26 and 29gave at least 50% control of Leptinotarsa decemlineata at a testconcentration of 0.03% active ingredient (w/v).

METHOD F: Screening Method to Test Activity of Compounds AgainstBlattella germanica.

Experimental compounds were diluted in an aqueous formulation containing5% DMSO and 0.1% Triton X100 and spread evenly on the inside surface oftest plates. After the plates dried, 10 adult male Blattella germanicawere added to each test plate. After 30 minutes, insects were removedfrom the treated surface and transferred to a clean plate containing acotton dental wick saturated with water. Plates were then held at 27° C.for 24 hours during which time the B. germanica were observed forknockdown and mortality. Plates treated with 5% DMSO and 0.1% TritonX100 served as controls. Compounds numbers 26 and 29 gave at least 50%control of Blattella germanica at a test concentration of 3 μgram activeingredient per cm².

METHOD G: Screening Method to Test Activity of Compounds AgainstReticulitermes flavipes and Tetramorium caespitum.

Experimental compounds were diluted in an aqueous formulation containing5% DMSO and 0.1% Triton X100 and spread evenly on the inside surface oftest plates. After the plates dried, 12-15 workers of Reticulitermesflavipes or Tetramorium caespitum were added to each test plate. After30 minutes, insects were removed from the treated surface andtransferred to a clean plate containing a cotton dental wick saturatedwith water. Plates were then held at 27° C. for 24 hours during whichtime the insects were observed for knockdown and mortality. Platestreated with 5% DMSO and 0.1% Triton X100 served as controls. Compoundsnumbers 26 and 29 gave at least 50% control of Reticulitermes flavipesat a test concentration of 3 μgram active ingredient per cm² and gave atleast 50% control of Tetramorium caespitum at a test concentration of0.3 μgram active ingredient per cm².

METHOD H: Phaedon cochleariae Test (Spray Application)

Solvent: 78 parts by weight of acetone 1.5 parts by weight ofdimethylformamide Emulsifier: 0.5 parts by weight of alkylarylpolyglycolether

To produce a suitable preparation of active compound, 1 part by weightof active compound is mixed with the stated amount of solvent andemulsifier, and the concentrate is diluted with emulsifier-containingwater to the desired concentration.

Chinese cabbage (Brassica pekinesis) leaf-disks are sprayed with apreparation of the active ingredient of the desired concentration. Oncedry, the leaf disks are infested with mustard beetle larvae (Phaedoncochleariae).

After the specified period of time, mortality in % is determined. 100%means that all beetle larvae have been killed and 0% means that none ofthe beetle larvae have been killed. In this test, for example, compounds1-32 and 34-46 from the preparation examples showed =80% activity at theconcentration of 500 g/ha.

METHOD I: Spodoptera frugiperda Test (Spray Application)

Solvent: 78 parts by weight acetone 1.5 parts by weightdimethylformamide Wetting agent 0.5 parts by weightalkylarylpolyglcolether

To produce a suitable preparation of the active compound, 1 part byweight of active compound is mixed with the stated amount of solvent andemulsifier, and the concentrate is dilutes with emulsifier-containingwater to the desired concentration.

Maize (Zea mais) leaf sections are sprayed with a preparation of theactive ingredient of the desired concentration. Once dry, the leafsections are infested with fall armyworm larvae (Spodoptera frugiperda).

After the specified period of time, mortality in % is determined. 100%means that all caterpillars have been killed and 0% means that none ofthe caterpillars have been killed.

In this test, for example, the following compounds from the preparationexamples showed =80% activity at the concentration of 500 g/ha 5, 10,15, 20, 22, 23, 24, 27, 28, 30, 34, 42, 46.

METHOD J: Myzus persicae Test (Spray Application)

Solvent: 78 parts by weight acetone 1.5 parts by weightdimethylformamide Wetting agent: 0.5 parts by weightalkylarylpolyglcolether

To produce a suitable preparation of active compound, 1 part by weightof active compound is mixed with the stated amount of solvent andemulsifier, and the concentrate is diluted with emulsifier-containingwater to the desired concentration.

Chinese cabbage (Brassica pekinesis) leaf-disks infected with allinstars of the green peach aphid (Myzus persicae), are sprayed with apreparation of the active ingredient at the desired concentration.

After the specified period of time, mortality in % is determined. 100%means that all aphids have been killed; 0% means that none of the aphidshave been killed.

In this test, for example, the following compounds from the preparationexamples showed =80% activity at the concentration of 500 g/ha: 1-12,14, 15-32, 34-40 and 42-46.

METHOD K: Tetranychus urticae Test; OP-Resistant (Spray Application)

Solvent: 78 parts by weight acetone 1.5 parts by weightdimethylformamide Wetting agent: 0.5 parts by weightalkylarylpolyglcolether

To produce a suitable preparation of active compound, 1 part by weightof active compound is mixed with the stated amount of solvent andemulsifier, and the concentrate is diluted with emulsifier-containingwater to the desired concentration.

French beans (Phaseolus vulgaris) which are heavily infested with allstages of the two spotted spidermite (Tetranychus urticae), are sprayedwith a preparation of the active ingredient at the desiredconcentration.

After the specified period of time, mortality in % is determined. 100%means that all spider mites have been killed and 0% means that none ofthe spider mites have been killed.

In this test, for example, the following compounds from the preparationexamples showed=80% activity at the concentration of 100 g/ha: 14, 20,24, 25, 26, 27, 28, 29, 30, 31, 32, 34, 37, 38, 39, 40, 42, 46

METHOD L: Frankliniella occidentalis Test (Spray Application)

Solvent: 78 parts by weight of acetone 1.5 parts by weight ofdimethylformamide Emulsifier: 0.5 parts by weight of alkylarylpolyglycolether

To produce a suitable preparation of active compound, 1 part by weightof active compound is mixed with the stated amount of solvent andemulsifier, and the concentrate is diluted with emulsifier-containingwater to the desired concentration.

French bean (Phaseolus vulgaris) leaf-disks are sprayed with a testsolution containing the desired concentration of the active ingredient.Once dry, the leaf disks are infested with western flower thrips(Frankliniella occidentalis).

After the specified period of time, mortality in % is determined. 100%means that all the thrips have been killed; 0% means that none of thethrips have been killed.

In this test, for example, the following compounds from the preparationexamples showed=80% activity at the concentration of 500 g/ha: 1-10, 12,16, 19-22, 25, 26, 28, 29, 31, 32, 34-36, 38-40, 42, 44-46.

METHOD M: Liriomyza trifolii Test (Spray Application)

Solvent: 78 parts by weight of acetone 1.5 parts by weight ofdimethylformamide Emulsifier: 0.5 parts by weight of alkylarylpolyglycolether

To produce a suitable preparation of active compound, 1 part by weightof active compound is mixed with the stated amount of solvent andemulsifier, and the concentrate is diluted with emulsifier-containingwater to the desired concentration.

French bean (Phaseolus vulgaris) leaf-disks infested with larvaes of theam. serpentine leaf miner (Liriomyza trifolii) are sprayed with a testsolution containing the desired concentration of the active ingredient.

After the specified period of time, mortality in % is determined. 100%means that all the leaf miners have been killed; 0% means that none ofthe leaf miners have been killed.

In this test, for example, the following compounds from the preparationexamples showed=80% activity at the concentration of 500 g/ha: 10, 15,34.

Having thus described in detail various embodiments of the presentinvention, it is to be understood that the invention defined by theabove paragraphs is not to be limited to particular details set forth inthe above description as many apparent variations thereof are possiblewithout departing from the spirit or scope of the present invention.

1. A 1-aryl-5-alkyl pyrazole compound of formula (I):

wherein: R₁ is hydrogen, cyano, halogen, R₈, formyl, —C(O)R₈, —C(O)OR₈,—C(O)NR₉R₁₀, or —C(S)NH₂; R₂ is R_(g) or —S(O)_(m)R₁₁; R₃ is methyl,ethyl or C₁-C₄ haloalkyl; R₄, R₅ and R₇ are independently hydrogen,halogen, alkyl, haloalkyl, cyano or nitro; R₆ is halogen, alkyl,haloalkyl, alkoxy, haloalkyloxy, cyano, nitro, —C(O)R₁₂, —S(O)_(n)R₁₂ orSF₅; Z is a nitrogen atom or C—R₁₃; R₈ is alkyl, haloalkyl, cycloalkylor halocycloalkyl; R₉ is hydrogen, alkyl, haloalkyl or alkoxy; R₁₀ ishydrogen, alkyl, haloalkyl or alkoxy; R₁₁ is alkyl, haloalkyl, alkenyl,haloalkenyl, alkynyl, haloalkynyl or cycloalkyl; R₁₂ is alkyl orhaloalkyl; R₁₃ is hydrogen, halogen, cyano, nitro, alkyl, haloalkyl,alkoxy or haloalkoxy; m is 0, 1 or 2; and n is 0, 1 or 2; or a saltthereof.
 2. The compound of claim 1, wherein: R₁ is hydrogen, cyano,halogen, R₈, formyl, —C(O)R₈, —C(O)OR₈, —C(O)NR₉R₁₀, or —C(S)NH₂; R₂ isC₁-C₄ alkyl, C₁-C₄ haloalkyl, or —S(O)_(m)R₁₁, R₃ is methyl, ethyl orC₁-C₄ haloalkyl, R₄, R₅ and R₇ are independently hydrogen, halogen,C₁-C₄ alkyl, C₁-C₄ haloalkyl, cyano or nitro; R₆ is halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyloxy, cyano, nitro,—C(O)R₁₂, —S(O)_(n)R₁₂ or SF₅; Z is a nitrogen atom or C—R₁₃; R₈ isC₁-C₄ alkyl, C₁-C₄ haloalkyl or cycloalkyl optionally substituted withone or more halogens; R₉ is hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl orC₁-C₄ alkoxy; R₁₀ is hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl or C₁-C₄alkoxy; R₁₁ is C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₂-C₄ alkenyl, C₂-C₄haloalkenyl, C₂-C₄ alkynyl, C₂-C₄ haloalkynyl or cycloalkyl; R₁₂ isC₁-C₄ alkyl or C₁-C₄ haloalkyl; R₁₃ is hydrogen, halogen, cyano, nitro,C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy or C₁-C₄ haloalkoxy; m is 0,1 or 2; and n is 0, 1 or 2; or a salt thereof.
 3. The compound of claim2, wherein: R₁ is hydrogen, cyano, fluoro, chloro, R₈, formyl, —C(O)R₈,—C(O)OR₈, —C(O)NR₉R₁₀, or —C(S)NH₂; R₂ is C₁-C₂ alkyl, C₁-C₂fluoroalkyl, C₁-C₂ chloroalkyl or —S(O)_(m)R₁₁; R₃ is methyl or ethyloptionally substituted with one to three halogens; R₄, R₅ and R₇ areindependently hydrogen, fluoro, chloro, C₁-C₂ alkyl, C₁-C₂ fluoroalkyl,C₁-C₂ chloroalkyl, cyano or nitro; R₆ is fluoro, chloro, C₁-C₂ alkyl,C₁-C₂ fluoroalkyl, C₁-C₂ chloroalkyl, C₁-C₂ alkoxy, C₁-C₂fluoroalkyloxy, C₁-C₂ chloroalkyloxy, cyano, nitro, —C(O)R₁₂,—S(O)_(n)R₁₂ or SF₅; Z is a nitrogen atom or C—R₁₃; R₈ is C₁-C₂ alkyl,C₁-C₂ fluoroalkyl or C₁-C₂ chloroalkyl; R₉ is hydrogen, C₁-C₂ alkyl,C₁-C₂ fluoroalkyl, C₁-C₂ chloroalkyl or C₁-C₂ alkoxy; R₁₀ is hydrogen,C₁-C₂ alkyl, C₁-C₂ fluoroalkyl, C₁-C₂ chloroalkyl or C₁-C₂ alkoxy; R₁₁is C₁-C₂ alkyl, C₁-C₂ fluoroalkyl, C₁-C₂ chloroalkyl, C₂-C₄ alkenyl,C₂-C₄ fluoroalkenyl, C₂-C₄ chloroalkenyl, C₂-C₄ alkynyl, C₂-C₄fluoroalkynyl or C₂-C₄ chloroalkynyl; R₁₂ is C₁-C₂ alkyl, C₁-C₂fluoroalkyl or C₁-C₂ chloroalkyl; R₁₃ is hydrogen, fluoro, chloro,cyano, nitro, C₁-C₂ alkyl, C₁-C₂ fluoroalkyl, C₁-C₂ chloroalkyl, C₁-C₂alkoxy, C₁-C₂ fluoroalkoxy or C₁-C₂ chloroalkoxy; m is 0, 1 or 2; and nis 0, 1 or 2; or a salt thereof.
 4. The compound of claim 2, wherein: R₁is cyano; R₂ is —S(O)_(m)R₁₁; R₃ is methyl or ethyl optionallysubstituted with one to three halogens; R₄, R₅, R₇ are independentlyhydrogen or halogen; R₆ is C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy or SF₅; R₁₁is C₁-C₄ haloalkyl; R₁₃ is C₁-C₄ alkyl optionally substituted with oneor more halogen atoms, or halogen; and m is 0, 1 or 2; or a saltthereof.
 5. The compound of claim 3, wherein: R₁ is cyano; R₂ is—S(O)_(m)R₁₁; R₃ is methyl, ethyl, —CH₂F or —CHF₂; R₄, R₅, and R₇ areindependently hydrogen, chloro or fluoro; R₆ is —CF₃, —OCF₃ or —SF₅; R₁₁is —CF₃, —CClF₂ or —CCl₂F; R₁₃ is methyl, chloro or fluoro; and m is 0,1 or 2; or a salt thereof.
 6. The compound of claim 3, wherein: R₁ iscyano; R₂ is —S(O)_(m)R₁₁; R₃ is methyl, ethyl, —CH₂F or —CHF₂; R₄ ishydrogen, Cl or F; R₅ and R₇ are both hydrogen; R₆ is —CF₃, —OCF₃ or—SF₅; R₁₁ is —CF₃, —CClF₂ or —CCl₂F; R₁₃ is methyl, chloro or fluoro;and m is 0, 1 or 2; or a salt thereof.
 7. The compound of claim 2,wherein: R₁ is cyano; R₂ is —S(O)_(m)R₁₁; R₃ is methyl or ethyl, R₄, R₅,R₇ are independently hydrogen or halogen; R₆ is C₁-C₄ haloalkyl, C₁-C₄haloalkoxy or SF₅; R₁₁ is C₁-C₄ haloalkyl; R₁₃ is C₁-C₄ alkyl optionallysubstituted with one or more fluoro or chloro, or halogen; and m is 0, 1or 2; or a salt thereof.
 8. The compound of claim 3, wherein: R₁ iscyano; R₂ is —S(O)_(m)R₁₁; R₃ is methyl or ethyl; R₄, R₅, and R₇ areindependently hydrogen, chloro or fluoro; R₆ is —CF₃, —OCF₃ or —SF₅; R₁₁is —CF₃, —CClF₂ or —CCl₂F; R₁₃ is methyl, chloro or fluoro; and m is 0,1 or 2; or a salt thereof.
 9. The compound of claim 3, wherein: R₁ iscyano; R₂ is —S(O)_(m)R₁₁; R₃ is methyl or ethyl; R₄ is hydrogen, Cl orF; R₅ and R₇ are both hydrogen; R₆ is —CF₃, —OCF₃ or —SF₅; R₁₁ is —CF₃,—CClF₂ or —CCl₂F; R₁₃ is methyl, chloro or fluoro; and m is 0, 1 or 2;or a salt thereof.
 10. The compound of claim 2, wherein: R₁ is cyano; R₂is —S(O)_(m)R₁₁; R₃ is methyl or ethyl substituted with one to threehalogens; R₄, R₅, and R₇ are independently hydrogen or halogen; R₆ isC₁-C₄ haloalkyl, C₁-C₄ haloalkoxy or —SF₅; R₁₁ is C₁-C₄ haloalkyl; R₁₃is C₁-C₄ alkyl or halogen; and m is 0, 1 or 2; or a salt thereof. 11.The compound of claim 3, wherein: R₁ is cyano; R₂ is —S(O)_(m)R₁₁; R₃ is—CH₂F, or —CHF₂; R₄ is hydrogen, fluoro or chloro; R₅ and R₇ are bothhydrogen; R₆ is —CF₃, —OCF₃ or SF₅; R₁₁ is —CF₃, —CClF₂ or —CCl₂F; R₁₃is methyl, fluoro or chloro; and m is 0, 1 or 2; or a salt thereof. 12.The compound of claim 3, wherein: R₁ is cyano; R₂ is —S(O)_(m)R₁₁; R₃ is—CH₂F, or —CHF₂; R₄ is Cl; R₅ and R₇ are both hydrogen; R₆ is —CF₃,—OCF₃ or —SF₅; R₁₁ is —CF₃, —CClF₂ or —CCl₂F; R₁₃ is chloro or fluoro;and m is 0, 1 or 2; or a salt thereof.
 13. A composition for treatmentof animals against ectoparasites comprising the compound of claim 1 andan acceptable carrier.
 14. The composition of claim 13, wherein thecomposition is in the form of a topical, dermal or subdermalformulation.
 15. The composition of claim 13, wherein the composition isin the form of a microemulsion, paste, pour-on formulation, ready-to-useformulation, spot-on formulation, oral solution, emulsion, injectablesolution, suspension or enteric formulation.
 16. The composition ofclaim 13, further comprising an additional pesticidally activeingredient.
 17. The composition of claim 16, wherein the additionalpesticidally active ingredient is selected from the group consisting ofarylpyrazoles, nodulisporic acid or derivatives thereof, macrocycliclactones, formamidines, pyrethroids, insect growth regulators,benzenedisulfonamide compounds, cestodal agents, pyridylmethylderivatives, depsipeptides, metaflumazone and mixtures thereof.
 18. Amethod for the therapeutic and/or prophylactic treatment of an animalagainst an ectoparasite and/or an endoparasite comprising administeringan effective amount of the compound of claim 1 to the animal in needthereof.
 19. The method of claim 18, wherein the treatment is against anectoparasite selected from the group consisting of arthropods, acarinaand mixtures thereof.
 20. The method of claim 18, wherein theectoparasite is selected from the group consisting of fleas, flies,lice, mites and ticks.
 21. The method of claim 18, wherein the treatmentis against an endoparasite.
 22. An insecticidal composition comprising acompound of formula I according to claim 1 and an acceptable carrier.23. A method for the preparation of the pesticidal composition of claim13 comprising mixing one or more compounds of the formula (I) accordingto claim 1 with one or more extenders and/or surface-active substances.24. A method for controlling pests, comprising contacting the pests ortheir environment with a compound of formula (I) according to claim 1 ora composition according to claim
 22. 25. The method of claim 24, whereinthe environment comprises plants, plant parts, seeds, soils, areas,materials or spaces.
 26. The method of claim 25, wherein transgenicplants are contacted with the compound.
 27. A process for thepreparation of the compound of claim 1, which comprises: (i) reacting acompound of formula (V)

with a compound of formula (IV)

wherein R^(A) is selected from alkylcarbonyl, alkoxycarbonyl, cyano andnitro; R₁ is hydrogen, cyano, halogen, R₈, formyl, —C(o)R₈, —C(o)NR₉R₁₀,or —C(s)NH₂; R₂ is R₈ or —S(O)_(m)R₁₁; R₄, R₅ and R₇ are independentlyhydrogen, halogen, alkyl, haloalkyl, cyano or nitro; R₆ is halogen,alkyl, haloalkyl, alkoxy, haloalkyloxy, cyano, nitro, —C(O)R₁₂,—S(O)_(m)R₁₂ or SF₅; Z is a nitrogen atom or C—R₁₃; R₈ is alkyl,haloalkyl, cycloalkyl or halocycloalkyl; R₉ is hydrogen, alkyl,haloalkyl or alkoxy; R₁₀ is hydrogen, alkyl, haloalkyl or alkoxy; R₁₁ islkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl orcycloalkyl; R₁₂ is alkyl or haloalkyl; R₁₃ is hydrogen, halogen, cyano,nitro, alkyl, haloalkyl, alkoxy or haloalkoxy; m is 0, 1 or 2; and n is0, 1 or 2; in the presence of a metal halide salt to form a compound offormula (III):

(ii) dehalogenating the compound of formula (III) to form a compound offormula (II):

(iii) oxidatively cleaving of compound of formula (II) to form acompound of claim (IIa):

(iv) reducing and halogenating the compound of formula (IIa) to form thecompound of formula (IIb):

and (v) optionally, further derivatizing the compound of formula (IIb)to form the compound of formula (I).
 28. A compound of formula (Ia):

wherein: R₁ is hydrogen, cyano, halogen, R₈, formyl, —C(O)R₈, —C(O)OR₈,—C(O)NR₉R₁₀, or —C(S)NH₂; R₂ is R₈ or —S(O)_(m)R₁₁; R₃ is a methyl orethyl, each optionally substituted with 1 to 3 halogens which may be thesame or different or —OH; R₄, R₅ and R₇ are independently hydrogen,halogen, alkyl, haloalkyl, cyano or nitro; R₆ is halogen, alkyl,haloalkyl, alkoxy, haloalkyloxy, cyano, nitro, —C(O)R₁₂, —S(O)_(n)R₁₂ orSF₅; Z is a nitrogen atom or C—R₁₃; R₈ is alkyl, haloalkyl, cycloalkylor halocycloalkyl; R₉ is hydrogen, alkyl, haloalkyl or alkoxy; R₁₀ ishydrogen, alkyl, haloalkyl or alkoxy; R₁₁ is alkyl, haloalkyl, alkenyl,haloalkenyl, alkynyl, haloalkynyl or cycloalkyl; R₁₂ is alkyl orhaloalkyl; R₁₃ is hydrogen, halogen, cyano, nitro, alkyl, haloalkyl,alkoxy or haloalkoxy; m is 0, 1 or 2; and n is 0, 1 or 2; or a saltthereof.
 29. A process for the preparation of the compound of claim 1,which comprises: (i) reacting a compound of formula (II):

 with a compound of formula R₂—Y to produce a compound of formula (III):

 wherein R_(a) is R₈, —O—R₈ or NR₉R₁₀ R₂ is R₈ or —S(O)_(m)R₁₁; R₃ ismethyl, ethyl or C₁-C₄ haloalkyl; R₈ is alkyl, haloalkyl, cycloalkyl orhalocycloalkyl; R₉ is hydrogen, alkyl, haloalkyl or alkoxy; R₁₀ ishydrogen, alkyl, haloalkyl or alkoxy; R₁₁ is alkyl, haloalkyl, alkenyl,haloalkenyl, alkynyl, haloalkynyl or cycloalkyl; m is 0, 1 or 2; and Yis a leaving group; (ii) reacting the compound of formula (III) with acompound of formula (Va) or salt thereof:

 to produce a compound of formula (VI):

 wherein Ra, R₂, R₃ are as defined above; and R₄, R₅ and R₇ areindependently hydrogen, halogen, alkyl, haloalkyl, cyano or nitro; R₆ ishalogen, alkyl, haloalkyl, alkoxy, haloalkyloxy, cyano, nitro, —C(O)R₁₂,—S(O)_(n)R₁₂ or SF₅; Z is a nitrogen atom or C—R₁₃; R₁₂ is alkyl orhaloalkyl; R₁₃ is hydrogen, halogen, cyano, nitro, alkyl, haloalkyl,alkoxy or haloalkoxy; and n is 0, 1 or 2; and (iii) optionallyde-esterifying the ester moiety of formula (VI), wherein R_(a) is O—R₈and R₈ is as defined above, by base catalyzed hydrolysis and subsequentacidification to form the compound corresponding to formula (VIa):

 and (iv) derivatizing the compound of formula (VIa) to produce thecompound of formula (I).
 30. The process of claim 29, wherein step (iv)is selected from the group consisting of: (a) a decarboxylation step;(b) reacting the compound of formula (VIa), with HNR₉R₁₀; (c) (i)reducing the —CO₂H moiety to —CH₂OH; (ii) oxidizing the —CH₂OH group toform —CHO; (iii) reacting the —CHO group with a Grignard reagentR₈—Mg-halogen; (iv) subjecting the compound to an additional oxidationstep; (d) (i) reacting the —CO₂H moiety of (VIa) with an reagent to formthe corresponding N-methoxy-N-methyl amide; and (ii) reacting theN-methoxy-N-methyl amide with a Grignard reagent R₈—Mg-halogen or anorganolithium reagent R₈—Li.
 31. A process for the preparation of thecompound of formula (I) of claim 1, which comprises:

(i) reacting the compound of formula (III) with hydrazine or saltthereof to form the compound of formula (IV):

 wherein R_(a) is R₈, —O—R₈ or NR₉R₁₀; R₂ and R₈ or —S(O)_(m)R₁₁; R₃ ismethyl, ethyl or C₁-C₄ haloalkyl; R₈ is alkyl, haloalkyl, cycloalkyl orhalocycloalkyl; R₉ is hydrogen, alkyl, haloalkyl or alkoxy; R₁₀ isalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl orcycloalkyl; m is 0, 1 is 2; and (ii) reacting the compound of formula(IV) with the compound of formula (Vb) to form the compound of formula(VI):

 wherein R_(a), R₂, are as defined above; R₄, R₅ and R₇ areindependently hydrogen, halogen, alkyl, haloalkyl, cyano or nitro; R₆ ishalogen, alkyl, haloalkyl, alkoxy, haloalkyloxy, cyano, nitro, —C(O)R₁₂,—S(O)_(n)R₁₂ or SF₅; Z is a nitrogen atom or C—R₁₃; R₁₂ is alkyl orhaloalkyl; R₁₃ is hydrogen, halogen, cyano, nitro, alkyl, haloalkyl,alkoxy or haloalkoxy; and n is 0, 1 or 2; and L is halogen,trifluoromethane sulfonyl, methanesulfonyl, or toluenesulfonyl; and(iii) optionally, subjecting the moiety —C(═O)R_(a) in the compound offormula (VI) to functional group modification.